ATR–Chk1 Pathway Inhibition Promotes Apoptosis after UV Treatment in Primary Human Keratinocytes: Potential Basis for the UV Protective Effects of Caffeine
Open accessAbstract
Novel approaches to prevent and reverse ultraviolet (UV) damage are needed to combat rising sunlight-induced skin cancer rates. Mouse studies have shown that oral or topical caffeine promotes elimination of UV-damaged keratinocytes via apoptosis and markedly inhibits subsequent skin cancer development. This potentially important therapeutic effect has not been studied in human skin cells. Here we use primary human keratinocytes to examine which of several caffeine effects mediates this process. In these cells, caffeine more than doubled apoptosis after 75 mJ/cm2 of UVB. Selectively targeting two of caffeine’s known effects did not alter UVB-induced apoptosis: inhibition of ATM (ataxia-telangiectasia mutated) and augmentation of cyclic AMP levels. In contrast, siRNA against ATR (ataxia-telangiectasia and Rad3-related) doubled apoptosis after UV through a p53-independent mechanism. Caffeine did not further augment apoptosis after UVB in cells in which ATR had been specifically depleted, suggesting a key target of caffeine in this effect is ATR. Inhibition of a central ATR target, Chk1, via siRNA or a novel highly specific inhibitor (PF610666) also augmented UVB-induced apoptosis. These data suggest that a relevant target of caffeine is the ATR-Chk1 pathway and that inhibiting ATR or Chk1 may have promise in preventing or reversing UV damage.
AI snapshot
Written from the paper’s full text.
TL;DR
In primary human keratinocytes, caffeine increased UVB-induced apoptosis, and the effect appeared to depend on inhibition of the ATR–Chk1 checkpoint pathway rather than ATM or cAMP. Knockdown or chemical inhibition of ATR/Chk1 also sensitized cells to UVB, largely independently of p53.
Key findings
- UVB at 75 mJ/cm² induced apoptosis in human keratinocytes; pretreatment with 2 mM caffeine raised apoptosis from 10% to 24% in one flow-cytometry measurement and gave a reproducible two- to three-fold increase across cultures.
- ATR siRNA reduced ATR protein by more than 90%, blocked UVB-induced Chk1 phosphorylation at Ser345, and doubled apoptosis; caffeine did not further increase apoptosis in ATR-depleted cells (50% without caffeine vs. 48% with caffeine).
- ATM siRNA, despite reducing ATM protein by about 70% and UVB-induced phospho-Ser1981 ATM by about 50%, did not affect UVB-induced apoptosis; dibutyryl cAMP up to 300 μM also had no effect.
- Chk1 siRNA reduced Chk1 protein by nearly 90% and increased cell death by 60% versus scrambled control; PF610666, a selective Chk1 inhibitor with Chk1 IC50 = 7 nM and cellular EC50 = 70 nM, augmented UVB-induced PARP cleavage and sub-2N DNA. p53 knockdown did not affect UVB-induced apoptosis and only modestly reduced the augmentation seen with ATR inhibition.
Methods
- Primary normal human keratinocytes were isolated from adult abdominal epidermis from two female patients (ages 37 and 66), cultured serum-free on collagen I, and used at passages 2–5.
- Cells were pretreated for 30 min with 2 mM caffeine, dibutyryl cAMP, or PF610666, then irradiated with 75 mJ/cm² UVB; siRNA against ATR, ATM, Chk1, p53, or scrambled control was nucleofected 48 h before UVB.
- Apoptosis was assessed by caspase-3 and PARP cleavage on Western blots, propidium iodide sub-2N DNA flow cytometry, and Annexin V staining; PF610666 potency and selectivity were measured with biochemical Chk1 kinase assays and a camptothecin checkpoint EC50 assay.
Limitations
- Stated: effective ATR inhibition in cultured cells required caffeine doses much higher than the plasma concentrations achieved in mice or humans, and the authors note that this in vitro versus in vivo difference remains unexplained.
- Stated: Chk1 siRNA increased UVB-induced apoptosis less strongly than ATR siRNA or PF610666; the authors suggest incomplete Chk1 knockdown, possible additional ATR targets, or partial off-target kinase inhibition by PF610666 at 1 μM.
- Evident: the study is in vitro with keratinocytes from two donors and does not provide human clinical or in vivo validation; the authors also note a p53-related discrepancy with prior cancer cell line and mouse studies.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
4 of 60 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Chemical or genetic inhibition of cell cycle checkpoint function sensitizes cancer cells to DNA damaging agents, including UV, ionizing radiation, alkylating agents, and topoisomerase inhibitors.
“Indeed, chemical or genetic inhibition of cell cycle checkpoint function sensitizes cancer cells to a wide variety of DNA damaging agents, including UV (Nghiem et al., 2001), ionizing radiation (Syljuasen et al., 2004), alkylating agents (Bunch and Eastman, 1996), and topoisomerase inhibitors (Shao et al., 1997).”
Quote in the paperSubstantial claim1 of 3 sources checked - Findingown data
Caffeine increased UVB-induced apoptosis in primary human keratinocytes, more than doubling it after 75 mJ/cm2 UVB.
“In these cells, caffeine more than doubled apoptosis after 75 mJ/cm2 of UVB.”
- Also stated in: § INTRODUCTION · plain
“We found that caffeine does indeed augment UVB-induced apoptosis in primary cultures of HKC.”
Quote in the paperSubstantial claim - Also stated in: § INTRODUCTION · plain
- Findingown data
Increasing cAMP levels with dibutyryl cAMP up to 300 μM did not affect UVB-induced apoptosis in human keratinocytes.
“While caffeine augmented UVB-induced apoptosis in HKC, doses of dibutyryl cAMP up to 300 μM had no effect (Figure 1d).”
Quote in the paperSubstantial claim - Findingown data
Reducing Chk1 expression with siRNA sensitized human keratinocytes to UVB-induced apoptosis.
“HKC with reduced expression of Chk1 were significantly sensitized to apoptosis induced by UVB (Figure 4a)”
Quote in the paperSubstantial claim- Rests on an assumption: ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
- Findingown data
Inhibiting ATM did not change UVB-induced apoptosis in primary human keratinocytes.
“In no case, however, did the addition of siRNA against ATM affect UVB-induced apoptosis (Figure 3b and c).”
Quote in the paperSubstantial claim
- Findingown data
Caffeine did not further increase apoptosis after UVB in human keratinocytes in which ATR had been depleted.
“However, there was no additive effect of caffeine on ATR-inhibited HKC (50% without caffeine, 48% with caffeine).”
Quote in the paperSubstantial claim - Findingown data
siRNA against ATR doubled apoptosis after UV in primary human keratinocytes.
“In contrast, siRNA against ATR (ataxia-telangiectasia and Rad3-related) doubled apoptosis after UV through a p53-independent mechanism.”
Quote in the paperSubstantial claim - Findingown data
UVB treatment of human keratinocytes with ATR inhibited by siRNA induced 50% apoptosis.
“UVB treatment of HKC in which ATR had been inhibited by siRNA induced 50% apoptosis.”
Quote in the paperSubstantial claim - Findingown data
PF610666 binds to the ATP binding pocket of Chk1 through hydrogen bonds with Cys87 and Glu85 in the hinge region.
“The compound binds to the ATP binding pocket through hydrogen bonds with Cys87 and Glu85 in the hinge region (Figure 4b, white asterisk on left).”
Quote in the paperNot a substantial claim - Findingown data
Chk1 inhibition by siRNA did not increase UVB-induced apoptosis to the same degree as caffeine or ATR siRNA.
“however, Chk1 inhibition by siRNA did not augment UVB-induced apoptosis to the same degree as caffeine or as ATR siRNA.”
Quote in the paperSubstantial claim- Rests on an assumption: ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
- Findingown data
UVB induced an increase in PARP cleavage in human keratinocytes.
“Additionally, UVB induced an increase in poly (adenosine diphosphate-ribose) polymerase (PARP) cleavage, a response that is dependent on caspase activation and the induction of apoptosis.”
Quote in the paperSubstantial claim - Findingown data
Genetic or chemical inhibition of the ATR-Chk1 pathway increased UVB-induced apoptosis in human keratinocytes.
“We found that genetic or chemical inhibition of the ATR-Chk1 pathway augmented UVB-induced apoptosis in a largely p53-independent manner in human keratinocytes.”
Quote in the paperSubstantial claim - Findingown data
Double knockdown of ATM and ATR markedly suppressed Chk2 phosphorylation, suggesting ATM function was significantly inhibited by siRNA.
“Indeed, double knockdown of ATM & ATR showed a marked suppression of Chk2 phosphorylation suggesting that ATM function was significantly inhibited by siRNA in these cells (Figure S2).”
Quote in the paperSubstantial claim - Findingown data
ATR knockdown potentiated the apoptotic effect of UVB in human keratinocytes.
“Consistent with the findings in Figure 2, ATR knockdown once again potentiated the apoptotic effect of UVB (Figure 3).”
Quote in the paperSubstantial claim - Findingown data
Treatment with 2 mM caffeine inhibited UVB-induced Chk1 phosphorylation at serine 345 in human keratinocytes.
“Indeed, treatment with 2 mM caffeine inhibited UVB-induced Chk1 phosphorylation at serine 345 (Figure 2a) suggesting that caffeine inhibits ATR under these conditions.”
Quote in the paperSubstantial claim - Findingown data
Known and plausible caffeine targets other than ATR-Chk1, including ATM and cAMP regulation, were not involved in the UV response in human keratinocytes.
“In contrast, other known and plausible targets of caffeine were not involved in the UV response including ATM and the regulation of cAMP levels.”
Quote in the paperSubstantial claim - Findingown data
There was a reproducible two- to three-fold increase in apoptosis when human keratinocytes were pretreated with caffeine.
“While the absolute number of cells undergoing UVB-induced apoptosis varied depending on the growth characteristics of the HKC culture (in particular, the passage number), we observed a reproducible two- to three-fold increase in apoptosis when cells were pretreated with caffeine (Figure 1c).”
Quote in the paperSubstantial claim - Findingown data
Electroporation of human keratinocytes with siRNA against Chk1 reduced Chk1 protein expression by nearly 90%.
“Electroporation of HKC with siRNA directed against Chk1 reduced protein expression by nearly 90% (Figure 4a).”
Quote in the paperSubstantial claim- Rests on an assumption: ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
- Findingown data
p53 protein induction blockade only slightly diminished the ability of ATR inhibition to increase apoptosis in HKC.
“and only modestly reduced the ability of ATR inhibition to augment apoptosis.”
Quote in the paperSubstantial claim - Findingown data
In HKC, exposure to 75 mJ/cm2 UVB strongly increased p53 protein levels at 8 hours.
“Treatment of HKC with 75 mJ/cm2 UVB strongly induced p53 protein levels at 8 h.”
Quote in the paperNot a substantial claim - Findingown data
The phenylbutanamide tail of PF610666 is immediately adjacent to the catalytic residue Asp148.
“The phenylbutanamide tail (Figure 4b, white asterisk on right) is immediately adjacent to the key catalytic residue Asp148.”
Quote in the paperNot a substantial claim - Findingown data
Replication checkpoint inhibition in primary human keratinocytes augmented cell death in a p53-independent manner.
“Consistent with the observed effects of caffeine in the mouse, we found that replication checkpoint inhibition in primary human keratinocytes augmented cell death in a p53-independent manner.”
Quote in the paperSubstantial claim - Findingown data
PF610666 is a potent, highly selective Chk1 inhibitor.
“Here we describe the characteristics and first use of a potent, highly selective Chk1 inhibitor, PF610666 (Figure 4b).”
Quote in the paperSubstantial claim - Findingown data
Flow cytometry showed the proportion of apoptotic cells increased from 10% in UVB-treated keratinocytes to 24% with caffeine.
“Using flow cytometry to quantitate apoptotic cells, the proportion of cells undergoing apoptosis increased from 10% in the UVB treated keratinocytes to 24% in cells treated with caffeine (Figure 1b).”
Quote in the paperSubstantial claim - Findingown data
Human keratinocytes with reduced Chk1 expression were significantly sensitized to UVB-induced apoptosis.
“HKC with reduced expression of Chk1 were significantly sensitized to apoptosis induced by UVB (Figure 4a)”
Quote in the paperSubstantial claim- Rests on an assumption: ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
- Findingown data
siRNA against ATM did not affect damage-induced phosphorylation of Thr-68 on Chk2.
“siRNA against ATM did not affect damage-induced phosphorylation of Thr-68 on Chk2 (a known target of ATM), but ATR is known to compensate for ATM in this process (Helt et al., 2005; Wang et al., 2006a).”
Quote in the paperSubstantial claim - Findingown data
The EC50 of PF610666 for cellular activity, measured as overriding the camptothecin-induced checkpoint, was 70 nM.
“Effective concentration 50 (EC50) of PF610666 for cellular activity measured as the ability to override the camptothecin-induced checkpoint was 70 nM.”
Quote in the paperNot a substantial claim - Findingown data
There was a 60% increase in cell death when comparing Chk1 siRNA to scrambled siRNA controls.
“We observed a 60% increase in cell death when comparing siRNA against Chk1 to scrambled siRNA controls.”
Quote in the paperSubstantial claim- Rests on an assumption: ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
- Findingown data
ATR knockdown markedly increased the proportion of HKC undergoing UVB-induced apoptosis.
“As in the previous experiments, knockdown of ATR markedly augmented the number of HKC that underwent UVB-induced apoptosis (Figure 5b and c).”
Quote in the paperSubstantial claim - Findingown data
Adding siRNA against ATM did not affect UVB-induced apoptosis in human keratinocytes.
“In no case, however, did the addition of siRNA against ATM affect UVB-induced apoptosis (Figure 3b and c).”
Quote in the paperSubstantial claim - Findingown data
p53 protein induction blockade did not alter UVB-induced apoptosis in HKC.
“Blocking p53 protein induction, however, had no effect on UVB-induced apoptosis in HKC”
Quote in the paperSubstantial claim - Findingown data
Propidium iodide and Annexin V staining of UVB-treated human keratinocytes revealed an increase in the percentage of cells undergoing apoptosis.
“Consistent with the activation of caspase 3, propidium iodide (Figures 1b and S1b) and Annexin V (Figure S1c) staining of UVB-treated HKC revealed an increase in the percentage of cells undergoing apoptosis.”
Quote in the paperSubstantial claim - Findingown data
Caffeine treatment increased UVB-induced cleavage of caspase 3 and PARP.
“Treatment with caffeine augmented UVB-induced cleavage of caspase 3 and PARP (Figure 1a).”
Quote in the paperSubstantial claim - Findingown data
Dibutyryl cAMP up to 300 μM had no effect on UVB-induced apoptosis in human keratinocytes.
“While caffeine augmented UVB-induced apoptosis in HKC, doses of dibutyryl cAMP up to 300 μM had no effect (Figure 1d).”
Quote in the paperSubstantial claim - Findingown data
Treatment of primary human keratinocytes with 75 mJ/cm2 UVB induced an apoptotic phenotype within 8 h, including caspase 3 cleavage.
“Treatment of primary human keratinocytes (HKC) with 75 mJ/cm2 of UVB induced an apoptotic phenotype within 8 h including cleavage of caspase 3 (Figures 1a and S1a).”
Quote in the paperSubstantial claim - Findingreasoning
siRNA against Chk1 increased UVB-induced apoptosis less robustly than siRNA against ATR.
“Augmentation of UVB-induced apoptosis by siRNA against Chk1 (Figure 4a) was not as robust as that by siRNA against ATR (Figure 2d).”
Quote in the paperNot a substantial claim - Findingown data
At 1 μM, PF610666 partially inhibits Chk2 and other kinases in vitro.
“Chk2 and other kinases are partially inhibited in vitro at this concentration of PF610666 (Table 1)”
Quote in the paperSubstantial claim - Findingown data
p53 knockdown did not increase UVB-induced apoptosis by ATR inhibition in HKC.
“In contrast, we found that p53 knockdown did not augment UVB-induced apoptosis by ATR inhibition in HKC (Figure 5b and c).”
Quote in the paperSubstantial claim - Findingown data
Caffeine markedly increased UVB-induced apoptosis in human keratinocytes.
“Indeed, we found that caffeine markedly augmented UVB-induced apoptosis in human keratinocytes (Figure 1).”
Quote in the paperSubstantial claim - Findingreasoning
Chk1 knockdown increased UVB-induced apoptosis less strongly than 1 μM PF610666.
“Similarly, Chk1 knockdown was not as strong as 1 μM PF610666 (Figure 4d) in augmenting UVB-induced apoptosis”
Quote in the paperNot a substantial claim - Findingown data
PF610666 is far more selective than UCN-01 for Chk1 inhibition.
“Here we show that a newly developed compound that is far more selective than UCN-01 for Chk1 inhibition (Table 1)”
Quote in the paperNot a substantial claim - Findingown data
PF610666 potently increased UVB-induced apoptosis.
“potently augmented UVB-induced apoptosis (Figure 4c and d).”
Quote in the paperSubstantial claim - Premisecitation
Oral administration of regular tea, but not decaffeinated tea, protected mice from UV carcinogenesis.
“Indeed, oral administration of regular tea but not decaffeinated tea was found to protect mice from UV carcinogenesis which led to subsequent direct tests of caffeine’s effects on this process (Huang et al., 1997; Lou et al., 1999).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Huang et al., 1997
- cites Lou et al., 1999 source
- Interpretationown data
Inhibiting ATR or Chk1 may be useful for preventing or reversing UV damage.
“These data suggest that a relevant target of caffeine is the ATR-Chk1 pathway and that inhibiting ATR or Chk1 may have promise in preventing or reversing UV damage.”
Quote in the paperSubstantial claim - Interpretationown data
The increase in apoptosis after UV caused by ATR siRNA occurs through a mechanism that does not require p53.
“In contrast, siRNA against ATR (ataxia-telangiectasia and Rad3-related) doubled apoptosis after UV through a p53-independent mechanism.”
Quote in the paperSubstantial claim - Interpretationcitation
Caffeine might inhibit skin carcinogenesis in humans.
“These studies imply that caffeine, one of the shared constituents of coffee and tea, might inhibit skin carcinogenesis in humans.”
Quote in the paperSubstantial claim - Interpretationown data
The ATR-Chk1 pathway is a relevant target of caffeine in the UVB response in human keratinocytes.
“These data suggest that a relevant target of caffeine is the ATR-Chk1 pathway and that inhibiting ATR or Chk1 may have promise in preventing or reversing UV damage.”
- Also stated in: § INTRODUCTION · hedged
“Instead, we found that the ATR-Chk1 pathway is the probable target of caffeine in this response because inhibition of ATR or Chk1 (checkpoint kinase 1) each phenocopied the effect of caffeine and augmented UVB-induced apoptosis in HKC.”
Quote in the paperSubstantial claim - Also stated in: § INTRODUCTION · hedged
- Premisecitation
In humans, coffee or tea consumption is associated with lower incidences of non-melanoma skin cancers in several epidemiologic studies.
“In humans, consumption of coffee or tea is associated with lower incidences of non-melanoma skin cancers in several epidemiologic studies (Abel et al., 2007; Hakim et al., 2000; Jacobsen et al., 1986; Rees et al., 2007).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Most of caffeine's effect on UVB-induced apoptosis in human keratinocytes under these conditions is mediated through ATR inhibition.
“The lack of an additive effect of caffeine treatment on ATR siRNA-treated HKC suggests that the majority of the caffeine effect under these conditions is through ATR inhibition.”
Quote in the paperSubstantial claim - Interpretationreasoning
PF610666 prevents Chk1 from phosphorylating its protein substrates.
“In this manner, PF610666 prevents Chk1 from phosphorylating its protein substrates.”
Quote in the paperSubstantial claim - Interpretationown data
Caffeine inhibits ATR under these UVB conditions in human keratinocytes.
“Indeed, treatment with 2 mM caffeine inhibited UVB-induced Chk1 phosphorylation at serine 345 (Figure 2a) suggesting that caffeine inhibits ATR under these conditions.”
Quote in the paperSubstantial claim - Premisecitation
Animal studies show that caffeine inhibits tumor formation in mice chronically treated with UV.
“animal studies showing that caffeine inhibits tumor formation in mice chronically treated with UV”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Huang et al., 1997
- cites Lu et al., 2002b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Zajdela and Latarjet, 1978
- Premisecitation
Topical caffeine applied to mouse skin after a single UVB dose increased apoptotic keratinocytes, measured by sunburn cells and other programmed cell death markers.
“We have previously shown that topical caffeine application to mouse skin after a single dose of UVB augmented the number of apoptotic keratinocytes as evaluated by sunburn cell formation and other markers of programmed cell death (Koo et al., 2007; Lu et al., 2002a).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Koo et al., 2007 source
- cites Lu et al., 2002a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Caffeine, administered orally or topically, inhibits tumor formation in high-risk UV-treated mice.
“Using this model, Conney and colleagues have shown that caffeine, when administered orally or topically, inhibits tumor formation in these high risk mice (Lou et al., 1999; Lu et al., 2002b).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Lou et al., 1999 source
- cites Lu et al., 2002b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Topical caffeine applied to mouse skin after UV irradiation may protect against UV-induced skin cancer development.
“and may provide protection from UV-induced skin cancer development.”
Quote in the paperSubstantial claim - Interpretationown data
ATM is not the relevant target of caffeine for UVB-induced apoptosis in human keratinocytes.
“Taken together, these data suggest that ATM is not the relevant target of caffeine for this process in HKC.”
Quote in the paperSubstantial claim - Premisecitation
Topical caffeine selectively induced apoptosis in nonmalignant tumors and squamous cell carcinomas without affecting neighboring normal non-tumor mouse skin, even long after UV exposure.
“Importantly, even long after completion of UV exposure, topical application of caffeine selectively induced apoptosis in nonmalignant tumors and squamous cell carcinomas without affecting neighboring normal “non-tumor” mouse skin (Lu et al., 2002b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lu et al., 2002b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
ATR is known to compensate for ATM in Chk2 phosphorylation.
“siRNA against ATM did not affect damage-induced phosphorylation of Thr-68 on Chk2 (a known target of ATM), but ATR is known to compensate for ATM in this process (Helt et al., 2005; Wang et al., 2006a).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Helt et al., 2005 source
- cites Wang et al., 2006a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationcitation
Topical caffeine applied to mouse skin after UV irradiation increases deletion of DNA-damaged keratinocytes.
“These findings suggest that topical application of caffeine to mouse skin after UV irradiation augments the deletion of DNA-damaged keratinocytes”
Quote in the paperSubstantial claim - Interpretationown data
Caffeine increases UVB-induced apoptosis in human keratinocytes through a mechanism separate from cAMP augmentation via phosphodiesterase inhibition.
“These data suggest that caffeine augments UVB-induced apoptosis in HKC through a separate mechanism than cAMP augmentation via phosphodiesterase inhibition.”
Quote in the paperSubstantial claim - Premisecitation
Primary human keratinocytes are much more susceptible to UVB-induced apoptosis than dermal fibroblasts.
“A recent study comparing primary human keratinocytes and dermal fibroblasts revealed that keratinocytes are far more susceptible to UVB-induced apoptosis than fibroblasts”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites D’Errico et al., 2003 source
- Interpretationown data
ATM is not the relevant target of caffeine for this process in human keratinocytes.
“Taken together, these data suggest that ATM is not the relevant target of caffeine for this process in HKC.”
Quote in the paperSubstantial claim - Premisecitation
Processes that are cAMP-dependent can typically be mimicked by significantly lower concentrations of dibutyryl cAMP, typically less than 100 μM.
“It is highly likely that caffeine’s effect on apoptosis is not dependent on cAMP because processes that are cAMP-dependent can typically be mimicked by significantly lower concentrations of dibutyryl cAMP (typically < 100 μM) (Wang et al., 2006b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2006b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
This mouse model resembles humans chronically exposed to UV early in life who have an increased risk of skin cancer later in life.
“This animal model resembles humans that are chronically exposed to UV early in life and have an increased risk of developing skin cancer later in life.”
Quote in the paperSubstantial claim - Interpretationreasoning
Caffeine's effect on apoptosis is not dependent on cAMP.
“It is highly likely that caffeine’s effect on apoptosis is not dependent on cAMP because processes that are cAMP-dependent can typically be mimicked by significantly lower concentrations of dibutyryl cAMP (typically < 100 μM) (Wang et al., 2006b).”
Quote in the paperSubstantial claim - Premisecitation
The response to UV in human keratinocytes differs significantly from that of other cell types more easily grown and widely used in UV studies.
“The response to UV in human keratinocytes (HKC) is significantly different from that of other cell types that are more easily grown and more widely used in UV studies (D’Errico et al., 2005; D’Errico et al., 2003) as detailed in the Discussion.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Caffeine inhibits ATM more potently than ATR, with IC50 values of 0.2 mM for ATM and 1.1 mM for ATR.
“Caffeine inhibits not only ATR, but also ATM even more potently (IC50 for ATM = 0.2 mM, IC50 for ATR = 1.1 mM) (Sarkaria et al., 1999).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sarkaria et al., 1999
- Premisecitation
Inhibition of ATM and especially ATR kinase might account for caffeine's observed effects in the hairless mouse model.
“Although caffeine is a known inhibitor of cyclic adenosine monophosphate (cAMP) phosphodiesterase (Butcher and Sutherland, 1962), the inhibition of ATM (ataxia-telangiectasia mutated) kinase and in particular ATR (ataxia-telangiectasia and Rad3-related) kinase (Blasina et al., 1999; Sarkaria et al., 1999) might account for the observed effects of caffeine in the hairless mouse model (Lu et al., 2”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Blasina et al., 1999 source
- cites Sarkaria et al., 1999
- cites Lu et al., 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The increase in UVB-induced apoptosis caused by ATR-Chk1 inhibition in human keratinocytes was largely independent of p53.
“What is clear and in agreement between these studies is that the majority of the apoptosis augmentation by ATR inhibition is p53-independent.”
- Also stated in: § DISCUSSION · boosted
“Here we have shown that inhibition of the ATR-Chk1 pathway by caffeine or a selective Chk1 inhibitor promotes culling of DNA-damaged human primary keratinocytes regardless of p53 status.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · boosted
- Premisecitation
Human epidemiologic studies associate coffee and tea consumption with lower rates of non-melanoma skin cancer.
“human epidemiologic studies linking coffee and tea consumption with lower rates of non-melanoma skin cancer”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationown data
UVB induces apoptosis in human keratinocytes.
“Taken together, activation of the caspase cascade and an increase in the percentage of cells with fragmented DNA suggests that UVB induces apoptosis in HKC.”
Quote in the paperSubstantial claim - Interpretationown data
The ATR-Chk1 pathway is the probable target of caffeine in the UVB response in human keratinocytes.
“Instead, we found that the ATR-Chk1 pathway is the probable target of caffeine in this response because inhibition of ATR or Chk1 (checkpoint kinase 1) each phenocopied the effect of caffeine and augmented UVB-induced apoptosis in HKC.”
Quote in the paperSubstantial claim - Interpretationown data
The culling of DNA-damaged human primary keratinocytes by ATR-Chk1 pathway inhibition occurs regardless of p53 status.
“Here we have shown that inhibition of the ATR-Chk1 pathway by caffeine or a selective Chk1 inhibitor promotes culling of DNA-damaged human primary keratinocytes regardless of p53 status.”
Quote in the paperSubstantial claim - Premisecitation
Oral caffeine given as drinking fluid at 0.4 mg/ml inhibits UV-induced skin carcinogenesis in mice.
“Oral administration of caffeine as drinking fluid (0.4 mg/ml) inhibits UV-induced skin carcinogenesis in mice (Huang et al., 1997).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Huang et al., 1997
- Interpretationown data
Caffeine's promotion of UVB-induced apoptosis seen in mouse keratinocytes also occurs in primary human keratinocytes.
“This finding suggests that caffeine’s promotion of UVB-apoptosis described in mouse keratinocytes also occurs in human primary keratinocytes.”
Quote in the paperSubstantial claim - Premisecitation
Effective ATR inhibition in cultured cells requires caffeine doses closer to those in cell-free kinase assays, where caffeine's IC50 against ATR is 1.1 mM.
“Our in vitro studies using keratinocytes are similar to other studies using cells in culture in which effective ATR inhibition requires caffeine doses closer to those required in cell-free in vitro kinase assays where the IC50 against ATR is 1.1 mM for caffeine (Sarkaria et al., 1999).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sarkaria et al., 1999
- Premisecitation
Oral caffeine (0.4 mg/ml, 2 mM) in drinking water markedly inhibited UVB-induced Chk1 Ser345 phosphorylation in mouse epidermis.
“Recently, Conney and colleagues showed that caffeine administered orally (0.4 mg/ml, 2 mM) with drinking water markedly inhibited the UVB-induced phosphorylation of Chk1 on Ser345 in the epidermis of mice (Lu et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lu et al., 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Topical caffeine applied to mice with multiple patches of p53-mutant skin cells enhanced elimination of these cells without further UVB irradiation.
“Topical applications of caffeine to mice with multiple patches of p53-mutant skin cells enhanced the elimination of these cells in the absence of further UVB irradiation (Lu et al., 2005b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lu et al., 2005b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Inhibition of the ATR-Chk1 pathway by caffeine or a selective Chk1 inhibitor promotes culling of DNA-damaged human primary keratinocytes.
“Here we have shown that inhibition of the ATR-Chk1 pathway by caffeine or a selective Chk1 inhibitor promotes culling of DNA-damaged human primary keratinocytes regardless of p53 status.”
Quote in the paperSubstantial claim - Interpretationreasoning
In live mice, plasma caffeine concentrations of 16 μM appear sufficient to inhibit ATR function in keratinocytes.
“Because Ser345-phosphorylation of Chk1 has been shown to be highly dependent on ATR function, this means that in vivo in the mouse, plasma concentrations of 16 μM appear to be sufficient to inhibit ATR function in keratinocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: Ser345 phosphorylation of Chk1 is highly dependent on ATR function.
- Interpretationreasoning
p53-mutant clones might be resistant to UV-induced apoptosis.
“These findings suggest that p53-mutant clones might be resistant to UV-induced apoptosis.”
Quote in the paperSubstantial claim- Rests on an assumption: Sun exposure increases the frequency and size of p53-mutant clones in skin.
- Premisecitation
The plasma caffeine concentration observed in mice matches the plasma concentration in humans (3.2 mg/l, 16 μM) who drink 2-5 cups of coffee daily.
“The observed plasma concentration of caffeine in mice is consistent with the plasma concentration in humans (3.2 mg/l, 16 μM) drinking 2–5 cups of coffee per day (de Leon et al., 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites de Leon et al., 2003 source
- Premisecitation
In mice receiving the cancer-preventive caffeine dose in drinking water (0.4 mg/ml, 2 mM), average plasma and epidermal caffeine concentrations over 24 hours are 16 μM and 16 nmol/g tissue, respectively.
“The plasma and epidermal concentrations of caffeine in mice receiving the cancer-preventive dose of caffeine in drinking water (0.4 mg/ml, 2 mM) is 16 μM and 16 nmol/g tissue, respectively, on average in a 24-hour-period (Conney et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Conney et al., 2007 source
- Classified as probably not a substantial claim. 13
- May combine two claims. 15
Classified as probably not a substantial claim.
PremisecitationBy coordinating cell cycle progression with DNA repair, cell cycle checkpoints help maintain genetic stability and prevent carcinogenesis.
“By coordinating cell cycle progression with DNA repair, cell cycle checkpoints help maintain genetic stability and prevent carcinogenesis (Abraham, 2001).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Abraham, 2001 source
May combine two claims.
PremisecitationNormal human skin contains clonal patches of p53-mutated keratinocytes in up to 4% of the epidermis, representing thousands of clones per person.
“Normal human skin carries clonal patches of p53-mutated keratinocytes in as much as 4% of the epidermis representing thousands of such clones per person (Jonason et al., 1996).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Jonason et al., 1996 source
The Results state that as much as 4% of sun-exposed normal epidermis contains p53-mutated keratinocytes and report clonal patches at 3–33 per cm². Those findings support frequent clones, but the paper does not give a whole-person estimate of thousands of clones; that number requires extrapolation from sampled skin. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrior studies in human cancer cell lines and mouse skin have shown that p53 disruption sensitizes cells to ATR inhibition.
“Prior studies in human cancer cell lines (Nghiem et al., 2001) and mouse skin (Lu et al., 2005b; Lu et al., 2004) have shown that p53 disruption sensitizes cells to inhibition of ATR.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites Nghiem et al., 2001 source
- cites Lu et al., 2005b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Lu et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Findingown dataTreating human keratinocytes with PF610666 increased UVB-induced PARP cleavage and the percentage of cells with sub-2N DNA content.
“Treatment of HKC with PF610666 augmented UVB-induced PARP cleavage at 8 h (Figure 4c) and increased the percentage of cells with sub-2N DNA content at 24 h (Figure 4d).”
Quote in the paperSubstantial claim- Rests on an assumption: ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
May combine two claims.
Findingown datasiRNA against ATR reduced ATR protein abundance by more than 90% and attenuated UVB-induced Chk1 phosphorylation.
“siRNA against ATR reduced the abundance of ATR protein by >90% and interfered with ATR signaling as judged by marked attenuation of UVB-induced Chk1 phosphorylation (Figure 2b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPF610666 is highly selective against Chk1, with an IC50 of 7 nM.
“The inhibitory effect of PF610666 was tested against a panel of human kinases and shown to be highly selective against Chk1 (IC50 = 7 nM; Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTargeting ATM with siRNA suppressed ATM protein expression by roughly 70% and inhibited UVB induction of active ATM by roughly 50%.
“By targeting ATM with siRNA, protein expression was suppressed by roughly 70%, and the induction by UVB of active ATM (phospho-Serine 1981 ATM) was inhibited by roughly 50% (Figure S2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataATR knockdown phenocopied caffeine's effects and increased UVB-induced caspase 3 and PARP cleavage in human keratinocytes.
“Knockdown of ATR phenocopied the effects of caffeine in HKC and augmented the UVB-induced increase in caspase 3 and PARP cleavage (Figure 2b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datap53 knockdown in HKC prevented UVB-induced p53 protein induction and lowered p53 protein below the pre-UVB baseline.
“Knockdown of p53 not only blocked this induction, but also suppressed p53 protein levels below the pre-UVB treatment baseline (Figure 5a).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataUV irradiation induced Chk1 phosphorylation maximally at 1 hour, and the signal was nearly gone by 8 hours.
“UV irradiation induced phosphorylation of Chk1 maximally at 1 h, and the phosphorylation signal was nearly lost by 8 h (Figure 2b and S1a).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationMuch of UV radiation's mutagenic and carcinogenic effects result from DNA damage in the form of cyclobutane pyrimidine dimers and 6-4 pyrimidine-pyrimidone photoproducts.
“Much of the mutagenic and carcinogenic effects of UV radiation are a consequence of DNA damage in the form of cyclobutane pyrimidine dimers and 6–4 pyrimidine-pyrimidone photoproducts (Brash et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Brash et al., 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationIn a study of 93,676 Caucasian women, each additional cup of caffeinated coffee was associated with a 5% decreased risk of non-melanoma skin cancer, while decaffeinated coffee showed no such benefit.
“In a recent study of 93,676 Caucasian women, each additional cup of caffeinated coffee ingested was associated with a 5% decreased risk of developing non-melanoma skin cancer while drinking de-caffeinated coffee showed no such benefit (Abel et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Abel et al., 2007 source
Classified as probably not a substantial claim.
PremisecitationCell cycle checkpoints are biochemical surveillance pathways that arrest cell cycle progression until essential events and/or DNA repair are complete.
“Cell cycle checkpoints are biochemical surveillance pathways that arrest cell cycle progression pending the completion of essential events and/or the repair of damaged DNA (Sancar et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sancar et al., 2004 source
May combine two claims.
PremisecitationHairless mice treated with UV twice weekly for twenty weeks had normal-appearing skin but were at higher risk for subsequent papillomas, keratoacanthomas, and squamous cell carcinomas.
“Hairless mice treated with UV twice weekly for twenty weeks had normal-appearing skin, but were at a higher risk for developing subsequent papillomas, keratoacanthomas and squamous cell carcinomas (Lou et al., 1999; Lu et al., 2002b).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Lou et al., 1999 source
- cites Lu et al., 2002b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUV exposure is the most important etiologic factor for non-melanoma skin cancer.
“Epidemiologic and molecular studies suggest exposure to ultraviolet (UV) light is the most important etiologic factor (Brash et al., 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Brash et al., 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUCN-01 was originally identified as an inhibitor of protein kinase C.
“Chemical inhibition of Chk1 has typically been carried out with UCN-01, originally identified as an inhibitor of protein kinase C (Busby et al., 2000; Wang et al., 1996).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Busby et al., 2000
- cites Wang et al., 1996 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrimary human keratinocytes are more UVB-resistant than dermal fibroblasts in proliferative capacity measured by colony survival assays.
“yet they are more UVB-resistant than fibroblasts in terms of their proliferative capacity as measured by colony survival assays (D’Errico et al., 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites D’Errico et al., 2003 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationKeratinocytes have greater UV-DNA repair capacity than fibroblasts through robust global genome repair.
“keratinocytes have a greater capacity (via robust global genome repair) for UV-DNA repair than fibroblasts”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites D’Errico et al., 2005 source
May combine two claims.
Interpretationown dataGenetic and chemical inhibition of Chk1 each phenocopied caffeine and ATR inhibition, supporting the importance of this pathway in the UV response and caffeine's effect.
“Taken together, genetic and chemical inhibition of Chk1 could each phenocopy the effect of caffeine and of ATR inhibition providing further support for the importance of this pathway in the UV response and in caffeine’s effect on this response.”
Quote in the paperSubstantial claim- Rests on an assumption: ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
May combine two claims.
Interpretationown dataATR is involved in the UVB response in human keratinocytes and is a relevant target of caffeine.
“Taken together, these data suggest that ATR is involved in the response to UVB in HKC and is a relevant target of caffeine.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCaffeine inhibits cAMP phosphodiesterase with an IC50 of 3 mM and increases cAMP levels in cells.
“Caffeine is an inhibitor of cAMP phosphodiesterase (IC50 = 3 mM) (Butcher and Sutherland, 1962) and it thus effectively increases levels of cAMP in cells.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Butcher and Sutherland, 1962 source
May combine two claims.
PremisecitationCaffeine's effect does not require p53, as p53 mutant patches of keratinocytes were selectively killed upon topical caffeine.
“Moreover, the effect of caffeine does not require p53 as p53 mutant patches of keratinocytes were selectively killed upon topical application of caffeine (Lu et al., 2005b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lu et al., 2005b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSimilar Chk1 phosphorylation kinetics have been observed and attributed to PPM1D, a phosphatase that dephosphorylates phospho-Chk1 at 8 hours or later after UV.
“Similar Chk1 phosphorylation kinetics have been observed in a recent study and attributed to PPM1D, a serine/threonine phosphatase whose expression is transcriptionally induced shortly after UV irradiation, and which dephosphorylates phospho-Chk1 at later time points (8 h or later post-UV) (Lu et al., 2005a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lu et al., 2005a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
PremisecitationUCN-01 has known off-target inhibitory effects on PKC and CDKs.
“Due to the known off-target inhibitory effects (ie: PKC and CDKs) of UCN-01 (Busby et al., 2000; Kawakami et al., 1996)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Busby et al., 2000
- cites Kawakami et al., 1996 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUCN-01 is a potent Chk1 inhibitor.
“UCN-01, originally identified as an inhibitor of protein kinase C, has been shown to be a potent Chk1 inhibitor (Busby et al., 2000; Wang et al., 1996).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Busby et al., 2000
- cites Wang et al., 1996 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationUCN-01 abrogates Chk1-dependent cellular responses and sensitizes cancer cells to several DNA-damaging agents, including mitomycin C, cisplatin, camptothecin, and 5-fluorouracil.
“Studies have shown that UCN-01 abrogates Chk1-dependent cellular responses and sensitizes cancer cells to several DNA damaging agents, including mitomycin C (Akinaga et al., 1993), cisplatin (Bunch and Eastman, 1996), camptothecin (Shao et al., 1997), and 5-fluorouracil (Hsueh et al., 1998).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Akinaga et al., 1993 source
- cites Bunch and Eastman, 1996
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Shao et al., 1997
The paper relies on this without support.
ATR carries out much of its DNA damage checkpoint signaling via the downstream kinase Chk1.
“In response to DNA damage, ATR mediates much of its checkpoint signaling through its downstream effector kinase Chk1.”
The paper relies on this without support.
Sun exposure increases the frequency and size of p53-mutant clones in skin.
“Sun exposure increases the frequency and size of the p53-mutant clones in skin.”
The paper relies on this without support.
Ser345 phosphorylation of Chk1 is highly dependent on ATR function.
“Ser345-phosphorylation of Chk1 has been shown to be highly dependent on ATR function”
The paper relies on this without support.
Non-melanoma skin cancers arise through UV-induced transformation of keratinocytes.
“Non-melanoma skin cancers arise via the transformation of keratinocytes induced by UV.”
The paper relies on this without support.
p53 is frequently mutated in non-melanoma skin cancers.
“p53 is frequently mutated in non-melanoma skin cancers”
The paper relies on this without support.
Chk1 is phosphorylated by ATR in response to UV.
“Chk1, which is phosphorylated by ATR in response to UV.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
UV-B irradiation activates diverse cellular responses in human cells, such as cell cycle arrest, DNA repair, and apoptosis through signal transduction pathways.
“UV-B irradiation activates diverse cellular responses in human cells, such as cell cycle arrest, DNA repair, and apoptosis through signal transduction pathways [15].”
From The Effect of Lycopene Preexposure on UV‐B‐Irradiated Human Keratinocytes (2016) · cites this paper as [15]
Cites
Dermatology in General Medicine.
(1987) · Annals of Internal Medicine · doi:10.7326/0003-4819-106-6-923_2 · Cited by 3,806 · see citing works
Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K., & Linn, S. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073723 · Cited by 3,317 · cited 1× · see citing works
“Cell cycle checkpoints are biochemical surveillance pathways that arrest cell cycle progression pending the completion of essential events and/or the repair of damaged DNA (Sancar et al., 2004).”
BackgroundAdenosine 3‘,5‘-Phosphate in Biological Materials
Butcher, R. W., & Sutherland, E. W. (1962) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)60316-3 · Cited by 2,077 · see citing works
Cell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966 · cited 1× · see citing works
“By coordinating cell cycle progression with DNA repair, cell cycle checkpoints help to maintain genetic stability and prevent carcinogenesis (Abraham, 2001).”
Background(1999) · PubMed · Cited by 1,030 · see citing works
Frequent clones of p53-mutated keratinocytes in normal human skin
Jonason, A. S., Kunala, S., Price, G. J., Restifo, R. J., Spinelli, H. M., Persing, J. A., Leffell, D. J., Tarone, R. E., & Brash, D. E. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.14025 · Cited by 685 · cited 1× · see citing works
“Normal human skin carries clonal patches of p53-mutated keratinocytes in as much as 4% of the epidermis representing thousands of such clones per person (Jonason et al., 1996).”
BackgroundUCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53
Wang, Q., Fan, S., Eastman, A., Worland, P. J., Sausville, E. A., & O'Connor, P. M. (1996) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/88.14.956 · Cited by 453 · cited 2× · see citing works
“UCN-01, originally identified as an inhibitor of protein kinase C, has been shown to be a potent Chk1 inhibitor (Wang et al., 1996; Busby et al., 2000).”
BackgroundTargeting the checkpoint kinases: chemosensitization versus chemoprotection
Zhou, B. S., & Bártek, J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1296 · Cited by 390 · cited 1× · see citing works
“However, recent studies have suggested that cell cycle checkpoints that are operational in cancer cells may reduce the effectiveness of many chemotherapeutic agents that function by inducing DNA damage (Zhou and Bartek, 2004).”
BackgroundPPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints
Lu, X., Nannenga, B., & Donehower, L. A. (2005) · Genes & Development · doi:10.1101/gad.1291305 · Cited by 389 · see citing works
Lu, Y.-P., Lou, Y.-R., Xie, J.-G., Peng, Q.-Y., Liao, J., Yang, C. S., Huang, M.-T., & Conney, A. H. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182429899 · Cited by 316 · see citing works
Self-citation(2000) · PubMed · Cited by 314 · see citing works
Caffeine inhibits the checkpoint kinase ATM
Blasina, A., Price, B. D., Turenne, G. A., & McGowan, C. H. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80486-2 · Cited by 295 · cited 1× · see citing works
“Although caffeine is a known inhibitor of cAMP phosphodiesterase (Butcher and Sutherland, 1962), the inhibition of ataxia–telangiectasia mutated (ATM) kinase and in particular ataxia–telangiectasia and Rad3-related (ATR) kinase (Blasina et al., 1999; Sarkaria et al., 1999) might account for the observed effects of caf…”
BackgroundSelf-citationNghiem, P., Park, P. K., Kim, Y.-S., Vaziri, C., & Schreiber, S. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.161281798 · Cited by 290 · cited 3× · see citing works
“checkpoint function sensitizes cancer cells to a wide variety of DNA-damaging agents, including UV (Nghiem et al., 2001), ionizing radiation (Syljuasen et al.”
BackgroundMethodInfluentialSelf-citation(1997) · PubMed · Cited by 238 · see citing works
(1996) · PubMed · Cited by 221 · see citing works
Blasina, A., Hallin, J. F., Chen, E., Arango, M. E., Kraynov, E. A., Register, J., Grant, S. K., Ninkovic, S., Chen, P., Nichols, T., et al. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-2391 · Cited by 220 · see citing works
Self-citation(1986) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/76.5.823 · Cited by 218 · cited 2× · see citing works
“In humans, consumption of coffee or tea is associated with lower incidences of nonmelanoma skin cancers in several epidemiological studies (Jacobsen et al., 1986; Hakim et al., 2000; Abel et al., 2007; Rees et al., 2007).”
BackgroundHelt, C. E., Cliby, W. A., Keng, P. C., Bambara, R. A., & O'Reilly, M. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410873200 · Cited by 216 · cited 1× · see citing works
“siRNA against ATM did not affect damage-induced phosphorylation of Thr-68 on Chk2 (a known target of ATM), but ATR is known to compensate for ATM in this process (Helt et al., 2005; Wang et al., 2006a).”
BackgroundChen, P., Luo, C., Deng, Y., Ryan, K., Register, J., Margosiak, S. A., Tempczyk-Russell, A., Nguyen, B., Myers, P., Lundgren, K., et al. (2000) · Cell · doi:10.1016/s0092-8674(00)80704-7 · Cited by 199 · see citing works
Separation of the epidermal sheet by dispase
Kitano, Y., & Okada, N. (1983) · British Journal of Dermatology · doi:10.1111/j.1365-2133.1983.tb01056.x · Cited by 191 · cited 1× · see citing works
“MATERIALS AND METHODS Cell lines and culture conditions Normal HKC were isolated from adult abdominal epidermis harvested from two female patients (age 37 and 66) as described previously (Kitano and Okada, 1983; Normand and Karasek, 1995; Boswell et al., 2007) in a protocol approved by the Massachusetts General Hospit…”
Method(1997) · PubMed · Cited by 177 · see citing works
Self-citationNormand, J., & Karasek, M. A. (1995) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/bf02634257 · Cited by 138 · cited 1× · see citing works
“MATERIALS AND METHODS Cell lines and culture conditions Normal HKC were isolated from adult abdominal epidermis harvested from two female patients (age 37 and 66) as described previously (Kitano and Okada, 1983; Normand and Karasek, 1995; Boswell et al., 2007) in a protocol approved by the Massachusetts General Hospit…”
MethodKawakami, K., Futami, H., Takahara, J., & Yamaguchi, K. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.0310 · Cited by 120 · cited 6× · see citing works
“Chemical inhibition of Chk1 has typically been carried out with UCN-01, originally identified as an inhibitor of protein kinase C (Wang et al., 1996; Busby et al., 2000).”
BackgroundInfluentialAkinaga, S., Nomura, K., Gomi, K., & Okabe, M. (1993) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00685833 · Cited by 118 · cited 1× · see citing works
“Studies have shown that UCN-01 abrogates Chk1-dependent cellular responses and sensitizes cancer cells to several DNAdamaging agents, including mitomycin C (Akinaga et al., 1993), cisplatin (Bunch and Eastman, 1996), camptothecin (Shao et al.”
BackgroundLou, Y.-R., Lu, Y.-P., Xie, J.-G., Huang, M.-T., & Conney, A. H. (1999) · Nutrition and Cancer · doi:10.1207/s15327914nc330205 · Cited by 105 · cited 3× · see citing works
“Hairless mice treated with UV twice weekly for 20 weeks had normal-appearing skin, but were at a higher risk for developing subsequent papillomas, keratoacanthomas, and squamous cell carcinomas (Lou et al., 1999; Lu et al., 2002b).”
BackgroundSelf-citationSyljuåsen, R. G., Sørensen, C. S., Nylandsted, J., Lukas, C., Lukas, J., & Bartek, J. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2434 · Cited by 99 · cited 1× · see citing works
“, 2001), ionizing radiation (Syljuasen et al., 2004), alkylating agents (Bunch and Eastman, 1996), and topoisomerase inhibitors (Shao et al.”
Background(2000) · PubMed · Cited by 88 · see citing works
Hsueh, C.-T., Kelsen, D. P., & Schwartz, G. K. (1998) · PubMed · Cited by 81 · see citing works
A pilot study of plasma caffeine concentrations in a US sample of smoker and nonsmoker volunteers
de Leon, J., Diaz, F. J., Rogers, T., Browne, D., Dinsmore, L., Ghosheh, O. H., Dwoskin, L. P., & Crooks, P. A. (2003) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(02)00348-2 · Cited by 77 · see citing works
ATR dependent activation of Chk2
Wang, X. Q., Redpath, J. L., Fan, S. T., & Stanbridge, E. J. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20700 · Cited by 73 · see citing works
Effect of Caffeine on the ATR/Chk1 Pathway in the Epidermis of UVB-Irradiated Mice
Lu, Y.-P., Lou, Y.-R., Peng, Q.-Y., Xie, J., Nghiem, P., & Conney, A. H. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5955 · Cited by 72 · cited 2× · see citing works
“, 1999) might account for the observed effects of caffeine in the hairless mouse model (Lu et al., 2008).”
BackgroundSelf-citationDaily coffee consumption and prevalence of nonmelanoma skin cancer in Caucasian women
Abel, E. L., Hendrix, S. O., McNeeley, S. G., Johnson, K. C., Rosenberg, C. A., Mossavar-Rahmani, Y., Vitolins, M., & Kruger, M. (2007) · European Journal of Cancer Prevention · doi:10.1097/01.cej.0000243850.59362.73 · Cited by 65 · cited 3× · see citing works
“In humans, consumption of coffee or tea is associated with lower incidences of nonmelanoma skin cancers in several epidemiological studies (Jacobsen et al., 1986; Hakim et al., 2000; Abel et al., 2007; Rees et al., 2007).”
BackgroundTea consumption and basal cell and squamous cell skin cancer: Results of a case-control study
Rees, J. R., Stukel, T. A., Perry, A. E., Zens, M. S., Spencer, S. K., & Karagas, M. R. (2007) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2006.11.038 · Cited by 65 · cited 2× · see citing works
“In humans, consumption of coffee or tea is associated with lower incidences of nonmelanoma skin cancers in several epidemiological studies (Jacobsen et al., 1986; Hakim et al., 2000; Abel et al., 2007; Rees et al., 2007).”
BackgroundD'Errico, M., Teson, M., Calcagnile, A., Nardo, T., De Luca, N., Lazzari, C., Soddu, S., Zambruno, G., Stefanini, M., & Dogliotti, E. (2005) · Cancer Research · doi:10.1158/0008-5472.432.65.2 · Cited by 64 · cited 1× · see citing works
“Moreover, keratinocytes have a greater ability (through robust global genome repair) for UV-DNA repair than fibroblasts, as might be expected from cells that are ‘‘professional’’ UVresponsive cells (D’Errico et al., 2005).”
BackgroundApoptosis and efficient repair of DNA damage protect human keratinocytes against UVB
D'Errico, M., Teson, M., Calcagnile, A., De Santis, L. P., Nikaido, O., Botta, E., Zambruno, G., Stefanini, M., & Dogliotti, E. (2003) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401224 · Cited by 62 · cited 1× · see citing works
“A recent study comparing primary HKC and dermal fibroblasts showed that keratinocytes are far more susceptible to UVB-induced apoptosis than fibroblasts; yet they are more UVB-resistant than fibroblasts in terms of their proliferative ability as measured by colony survival assays (D’Errico et al., 2003).”
BackgroundLu, Y., Lou, Y.-R., Peng, Q., Xie, J., & Conney, A. H. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0760 · Cited by 59 · see citing works
Self-citationProtection from photodamage by topical application of caffeine after ultraviolet irradiation
Koo, S.-W., Hirakawa, S., Fujii, S., Kawasumi, M., & Nghiem, P. (2007) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2007.07812.x · Cited by 58 · cited 1× · see citing works
“We have shown previously that topical caffeine application to mouse skin after a single dose of UVB augmented the number of apoptotic keratinocytes as evaluated by sunburn cell formation and other markers of programmed cell death (Lu et al., 2002a; Koo et al., 2007).”
BackgroundSelf-citationCONNEY, A., ZHOU, S., LEE, M., XIE, J., YANG, C., LOU, Y., & LU, Y. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2006.11.001 · Cited by 53 · cited 1× · see citing works
“4 mg ml (1), 2 mM) is 16mM and 16 nmol g 1 tissue, respectively, on average in a 24-hour period (Conney et al., 2007).”
BackgroundSelf-citationLu, Y.-P., Lou, Y.-R., Liao, J., Xie, J., Peng, Q.-Y., Yang, C. S., & Conney, A. H. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi086 · Cited by 53 · see citing works
Self-citationThe Protective Role of a Small GTPase RhoE against UVB-induced DNA Damage in Keratinocytes
Boswell, S. A., Ongusaha, P. P., Nghiem, P., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m610532200 · Cited by 40 · cited 1× · see citing works
“MATERIALS AND METHODS Cell lines and culture conditions Normal HKC were isolated from adult abdominal epidermis harvested from two female patients (age 37 and 66) as described previously (Kitano and Okada, 1983; Normand and Karasek, 1995; Boswell et al., 2007) in a protocol approved by the Massachusetts General Hospit…”
MethodSelf-citationStimulatory effect of topical application of caffeine on UVB-induced apoptosis in mouse skin.
Lu, Y., Lou, Y.-R., Li, X., Xie, J., Lin, Y., Shih, W. J., & Conney, A. H. (2002) · PubMed · Cited by 39 · see citing works
Self-citationWang, Y., Kim, P. K. M., Peng, X., et al. (2006) · APOPTOSIS · doi:10.1007/s10495-005-4293-6 · Cited by 19 · cited 2× · see citing works
“…by UVB of active ATM (phospho-Serine 1981 ATM) was inhibited by roughly 50% (Figure S2). siRNA against ATM did not affect damage-induced phosphorylation of Thr-68 on Chk2 (a known target of ATM), but ATR is known to compensate for ATM in this process (Helt et al., 2005; Wang et al., 2006a).”
Background(1978) · PubMed · Cited by 18 · see citing works
Flagged first, then by citations
8 of the 51 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Brash, 2008, Carcinogenesis: ultraviolet radiation, vol. 1, 999
- Jacobsen, 1986, Coffee drinking, mortality, and cancer incidence: results from a Norwegian prospective study, J Natl Cancer Inst, 76, 823
Cited by
Sorted by citations
Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics
Ma, C. X., Janetka, J. W., & Piwnica-Worms, H. M. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.10.009 · Cited by 271 · see citing works
“In contrast to the other CHK1 inhibitors, PF477736 treatment causes a decrease in CHK1 S345 phosphorylation [65].”
ResultCaffeine’s Mechanisms of Action and Its Cosmetic Use
Herman, A., & Herman, A. P. (2012) · Skin Pharmacology and Physiology · doi:10.1159/000343174 · Cited by 248 · see citing works
de Feraudy, S. M., Revet, I. M., Bezrookove, V., Feeney, L., & Cleaver, J. E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002175107 · Cited by 195 · see citing works
“In contrast, treatmentwith caffeine (1mM) that inhibits the ATR–CHK1 pathway (31, 32) increased the levels Table 2.”
BackgroundInfluentialEpidemiologia do carcinoma basocelular
Chinem, V. P., & Miot, H. A. (2011) · Anais Brasileiros de Dermatologia · doi:10.1590/s0365-05962011000200013 · Cited by 196 · see citing works
The ATR barrier to replication-born DNA damage
Lopez-Contreras, A. J., & Fernández-Capetillo, Ó. (2010) · DNA repair · doi:10.1016/j.dnarep.2010.09.012 · Cited by 138 · see citing works
Functional relevance of the histone γH2Ax in the response to DNA damaging agents
Revet, I. M., Feeney, L., Bruguera, S., Wilson, W., Dong, T. K., Oh, D. H., Dankort, D. L., & Cleaver, J. E. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105866108 · Cited by 133 · see citing works
“Survival of mutant cells following UV damage, either grown with or without caffeine that inhibits the ATR-Chk1 pathway (26, 27), was also not different from wild-type.”
BackgroundResultγH2Ax: Biomarker of Damage or Functional Participant in DNA Repair “All that Glitters Is not Gold!”
Cleaver, J. E. (2011) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2011.00995.x · Cited by 112 · see citing works
“ATM was more sensitive than ATR to caffeine, but in vivo ATM seems refractory and the target of caffeine is ATR (35,36).”
BackgroundInfluentialDeciphering UV‐induced DNA Damage Responses to Prevent and Treat Skin Cancer
Lee, J. W., Ratnakumar, K., Hung, K., Rokunohe, D., & Kawasumi, M. (2020) · Photochemistry and Photobiology · doi:10.1111/php.13245 · Cited by 112 · see citing works
“but addition of caffeine to these cells had no additive effect on apoptosis (180).”
BackgroundSelf-citationATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1
Hilton, B. A., Li, Z., Musich, P. R., Wang, H., Cartwright, B. M., Serrano, M., Zhou, X. Z., Lu, K. P., & Zou, Y. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.08.008 · Cited by 95 · see citing works
“Since ATR is well known for its DDR role in the nucleus, including apoptosis suppression via the ATR-Chk1 pathway (Heffernan et al., 2009), this study reveals a Pin1-regulated function of ATR in the cytoplasm.”
Wang, J., He, J., Su, F., Ding, N., Hu, W., Yao, B. W., Wang, W., & Zhou, G. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.227 · Cited by 92 · see citing works
Increased Caffeine Intake Is Associated with Reduced Risk of Basal Cell Carcinoma of the Skin
Song, F., Qureshi, A. A., & Han, J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3511 · Cited by 88 · see citing works
Fuhrmann, T., Smith, N., & Tausk, F. (2010) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2009.12.009 · Cited by 78 · see citing works
Skin Protection by Carotenoid Pigments
Flieger, J., Raszewska-Famielec, M., Radzikowska-Büchner, E., & Flieger, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031431 · Cited by 75 · see citing works
Caini, S., Cattaruzza, M. S., Bendinelli, B., Tosti, G., Masala, G., Gnagnarella, P., Assedi, M., Stanganelli, I., Palli, D., & Gandini, S. (2016) · Zeitschrift für Ernährungswissenschaft · doi:10.1007/s00394-016-1253-6 · Cited by 74 · see citing works
Quinet, A., Vessoni, A. T., Rocha, C. R. R., Gottifredi, V., Biard, D., Sarasin, A., Menck, C. F. M., & Stary, A. (2014) · DNA Repair · doi:10.1016/j.dnarep.2013.12.005 · Cited by 70 · see citing works
The 6-4 Photoproduct Is the Trigger of UV-Induced Replication Blockage and ATR Activation
Hung, K.-F., Sidorova, J. M., Nghiem, P., & Kawasumi, M. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1917196117 · Cited by 64 · see citing works
“The cancer-preventive effect of ATR inhibition is likely due in part to increased UVinduced apoptosis (27), which eliminates damaged skin cells that are prone to incorporating DNA mutations and are more likely to undergo malignant transformation.”
BackgroundSelf-citationCaffeine Promotes Ultraviolet B-induced Apoptosis in Human Keratinocytes without Complete DNA Repair
Han, W., Ming, M., & He, Y. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.222349 · Cited by 66 · see citing works
Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin
Kemp, M. G., Spandau, D. F., & Travers, J. B. (2017) · Molecules · doi:10.3390/molecules22030356 · Cited by 62 · see citing works
The effects of caffeine on wound healing
Ojeh, N. O., Stojadinović, O., Pastar, I., Sawaya, A. P., Yin, N. C., & Tomic‐Canic, M. (2014) · International Wound Journal · doi:10.1111/iwj.12327 · Cited by 62 · see citing works
HMGA2 Inhibits Apoptosis through Interaction with ATR-CHK1 Signaling Complex in Human Cancer Cells
Natarajan, S., Hombach‐Klonisch, S., Dröge, P., & Klonisch, T. C. (2013) · Neoplasia · doi:10.1593/neo.121988 · Cited by 59 · see citing works
Gherardini, J., Wegner, J., Chéret, J., Ghatak, S., Lehmann, J., Alam, M., Jimenez, F., Funk, W., Böhm, M., Botchkareva, N. V., et al. (2019) · International Journal of Cosmetic Science · doi:10.1111/ics.12521 · Cited by 56 · see citing works
The Effect of Lycopene Preexposure on UV‐B‐Irradiated Human Keratinocytes
Ascenso, A., Pedrosa, T., Pinho, S., Pinho, F., Oliveira, J. M. P. F. D., Cabral Marques, H., Oliveira, H., Simões, S., & Santos, C. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/8214631 · Cited by 57 · see citing works
“Through lipid peroxidation, protein cross-linking, and DNA damage, UV-A and UV-B radiation (UVR) can cause photoaging and photocarcinogenesis [1–3].”
BackgroundInfluentialPredicting the Risk of a Second Basal Cell Carcinoma
Verkouteren, J. A. C., Smedinga, H., Steyerberg, E. W., et al. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.244 · Cited by 56 · see citing works
“In vitro research on human keratinocytes has demonstrated that this inhibitory effect of caffeine may be due to the induction of apoptosis in UVB-damaged keratinocytes (Heffernan et al., 2009; Han et al., 2011).”
BackgroundKawasumi, M., Lemos, B. D., Bradner, J. E., Thibodeau, R. M., Kim, Y.-S., Schmidt, M. N., Higgins, E., Koo, S., Angle-Zahn, A., Chen, A., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1111378108 · Cited by 59 · see citing works
“Specifically, ATR-kd expression (24, 25), decreased ATR expression attributable to Seckel mutation (26, 27), and ATR knockdown by siRNA (28) all showed hypersensitivity to UV and decreased phosphorylation of Chk1.”
Self-citationFrauenstein, K., Sydlik, U., Tigges, J., Majora, M., Wiek, C., Hanenberg, H., Abel, J., Esser, C., Fritsche, E., Krutmann, J., et al. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2013.102 · Cited by 56 · see citing works
“Inhibition of AHR signaling increases the rate of UVB-induced apoptosis in human KC.”
BackgroundInfluentialUVB and Caffeine: Inhibiting the DNA Damage Response to Protect Against the Adverse Effects of UVB
Kerzendorfer, C., & O’Driscoll, M. (2009) · Journal of Investigative Dermatology · doi:10.1038/jid.2009.99 · Cited by 49 · see citing works
Mechanisms of Caffeine-Induced Inhibition of UVB Carcinogenesis
Conney, A. H., Lu, Y.-P., Lou, Y.-R., Kawasumi, M., & Nghiem, P. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00144 · Cited by 47 · see citing works
“Taken from Heffernan et al. (2009). www.frontiersin.org June 2013 | Volume 3 | Article 144 | 5 UVB (30 mJ/cm2) Caffeine (2.1 mmol/L) Caffeine SB (2.1 mmol/L) P-Chk1 (Ser345) P-Chk2 (Thr68) Cyclin B1 p-Cyclin B1 (Ser147) Ac n Phospho-Chk1 (Ser345) Water CF CSB UVB Water UVB CF UVB CSB 153% é 201%…”
BackgroundResultInfluentialSelf-citationMouse models for ATR deficiency
O’Driscoll, M. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.09.001 · Cited by 40 · see citing works
Targeting Protective Autophagy Exacerbates UV-Triggered Apoptotic Cell Death
Chen, L.-H., Chu, P., Lee, Y., Tu, P., Chi, C., Lee, H., & Chiou, S. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13011209 · Cited by 42 · see citing works
“On the other hand, previous studies have reported that ATR inhibition promoted apoptosis induced by UV [21,22].”
BackgroundCoffee Consumption and Melanoma: A Systematic Review and Meta-Analysis of Observational Studies
Yew, Y. W., Lai, Y. C., & Schwartz, R. A. (2015) · American Journal of Clinical Dermatology · doi:10.1007/s40257-015-0165-1 · Cited by 41 · see citing works
Oh, C. C., Jin, A., Yuan, J., & Koh, W. (2019) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2019.01.084 · Cited by 36 · see citing works
Sun, Y., Wang, P., Li, H., & Dai, J. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26859 · Cited by 36 · see citing works
“CHK1 further transduces signals by phosphorylating its downstream effector proteins, such as cdc25 and p53 (Heffernan et al., 2009, 2002; Sancar, Lindsey‐Boltz, Unsal‐Kacmaz, & Linn, 2004).”
Chang, E. T., Parekh, P. R., Yang, Q., Nguyen, D. M., & Carrier, F. (2016) · Oncotarget · doi:10.18632/oncotarget.7020 · Cited by 35 · see citing works
“In fact, levels of HIF-1α correlate with melanoma growth [18], and inhibition of ATR has been shown to increase apoptosis in UV-exposed primary human keratinocytes [19].”
Kemp, M. G., & Sancar, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.719740 · Cited by 33 · see citing works
“4C, inhibition of ATR sensitized cycling HaCaT cells to the killing effects of UV, which is consistent with previous reports (7, 8, 10, 21).”
ResultChou, F.-J., Chen, Y., Chen, D., Niu, Y., Li, G., Keng, P., Yeh, S., & Chang, C. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2018.12.050 · Cited by 29 · see citing works
“Bypassing cell cycle arrest causes chromosome segregation without complete repair, which might lead to mitotic catastrophe and result in activation of cell apoptosis [29].”
BackgroundA Frog Peptide Ameliorates Skin Photoaging Through Scavenging Reactive Oxygen Species
Feng, G., Wei, L., Che, H., Shen, Y., Yang, J., Mi, K., Liu, J., Wu, J., Yang, H., & Mu, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.761011 · Cited by 30 · see citing works
“It has been shown that UVB radiation causes DNA damage such as cyclobutane pyrimidine dimers and six to four pyrimidine-pyrimidone photoproducts (Heffernan et al., 2009), and then the damage induces phosphorylation of the Ser-139 residue of the histone variant H2AX, forming γH2AX.”
BackgroundLi, L., Li, M., Xu, S., Chen, H., Chen, X., & Gu, H. (2019) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2019.03.010 · Cited by 30 · see citing works
Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case–control study
Ferrucci, L. M., Cartmel, B., Molinaro, A. M., Leffell, D. J., Bale, A. E., & Mayne, S. T. (2014) · European Journal of Cancer Prevention · doi:10.1097/cej.0000000000000037 · Cited by 30 · see citing works
“Additional research on caffeine and UVB-irradiated human keratinocytes has found similar proapoptotic effects (Heffernan et al., 2009; Han et al., 2011).”
BackgroundLu, Y.-P., Lou, Y.-R., Peng, Q.-Y., Nghiem, P., & Conney, A. H. (2011) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-11-0116 · Cited by 30 · see citing works
Self-citationConney, A. H., Lou, Y.-R., Nghiem, P., Bernard, J. J., Wagner, G. C., & Lu, Y.-P. (2012) · Topics in current chemistry · doi:10.1007/128_2012_336 · Cited by 29 · see citing works
“In addition, inhibition of the ATR/Chk-1 pathway by caffeine was associated with enhanced UVBinduced apoptosis in primary human keratinocytes [18].”
BackgroundSelf-citationLatosińska, J. N., Latosińska, M., Olejniczak, G. A., Seliger, J., & Žagar, V. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci5004224 · Cited by 26 · see citing works
LaGory, E. L., Sitailo, L. A., & Denning, M. F. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.055392 · Cited by 26 · see citing works
Miura, K., Hughes, M. C. B., Green, A. C., & van der Pols, J. C. (2013) · European Journal of Nutrition · doi:10.1007/s00394-013-0556-0 · Cited by 27 · see citing works
Mavrogonatou, E., Angelopoulou, M. T., Rizou, S. V., Pratsinis, H., Gorgoulis, V. G., & Kletsas, D. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05106-y · Cited by 24 · see citing works
Ma, H., Yu, M., Lei, M., Tan, F., & Li, N. (2015) · AAPS PharmSciTech · doi:10.1208/s12249-014-0278-5 · Cited by 23 · see citing works
“The ultraviolet B radiation (UVB), a minor component of sunlight, should bear the main responsibility for this phenomenon (2).”
BackgroundMethodA New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?
Lang, P. Y., & Gershon, T. R. (2018) · BioEssays · doi:10.1002/bies.201700243 · Cited by 20 · see citing works
Tokez, S., Alblas, M., Nijsten, T. E. C., Pardo, L. M., & Wakkee, M. (2019) · British Journal of Dermatology · doi:10.1111/bjd.18810 · Cited by 19 · see citing works
Seliger, J., Žagar, V., Apih, T., Gregorovič, A., Latosińska, M., Olejniczak, G. A., & Latosińska, J. N. (2016) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2016.01.025 · Cited by 18 · see citing works
Elias, M. L., Israeli, A. F., & Madan, R. K. (2023) · Indian Journal of Dermatology · doi:10.4103/ijd.ijd_166_22 · Cited by 20 · see citing works
Voriconazole enhances UV‐induced DNA damage by inhibiting catalase and promoting oxidative stress
Lee, V., Gober, M. D., Bashir, H. M., O'Day, C., Blair, I. A., Mesaros, C., Weng, L., Huang, A., Chen, A., Tang, R., et al. (2019) · Experimental Dermatology · doi:10.1111/exd.14038 · Cited by 17 · see citing works
Hezaveh, E., Jafari, S., Jalilpiran, Y., Zargarzadeh, N., Mahdavi, R., & Gargari, B. P. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.2016600 · Cited by 18 · see citing works
Takikawa, M., Sumi, Y., Tanaka, Y., et al. (2012) · Journal of Radiation Research · doi:10.1269/jrr.11193 · Cited by 15 · see citing works
Zanetti, T. A., Biazi, B. I., Coatti, G. C., et al. (2019) · Toxicology in Vitro · doi:10.1016/j.tiv.2019.104643 · Cited by 14 · see citing works
Chiang, H., Chen, C.-W., Chen, C., Wang, H.-W., Jhang, J.-H., Huang, Y.-H., & Wen, K. (2014) · Coffee in Health and Disease Prevention · doi:10.1016/b978-0-12-409517-5.00058-9 · Cited by 13 · see citing works
Bioactives in Nutricosmetics: A Focus on Caffeine from Tea to Coffee
Blanco-Llamero, C., Macário, H. F., Guedes, B. N., Fathi, F., Oliveira, M. B. P. P., & Souto, E. B. (2024) · Cosmetics · doi:10.3390/cosmetics11050149 · Cited by 11 · see citing works
Shaj, K., Hutcherson, R. J., & Kemp, M. G. (2019) · Photochemistry and Photobiology · doi:10.1111/php.13164 · Cited by 9 · see citing works
Physiological effects of coffee and human health. A review
Nehlig, A. (2012) · Cahiers Agricultures · doi:10.1684/agr.2012.0549 · Cited by 9 · see citing works
Li, Z., Wang‐Heaton, H., Cartwright, B. M., Makinwa, Y., Hilton, B., Musich, P. R., Shkriabai, N., Kvaratskhelia, M., Guan, S., Chen, Q., et al. (2021) · The FASEB Journal · doi:10.1096/fj.202001636rrr · Cited by 9 · see citing works
Seleem, M. M., Abulfadl, Y. S., Hoffy, N., Lotfy, N. M., & Ewida, H. A. (2022) · Future Journal of Pharmaceutical Sciences · doi:10.1186/s43094-022-00417-5 · Cited by 7 · see citing works
“Moreover, the results regarding the effect of caffeine on beta cyclin are controversial [43], whereas in one study caffeine was found to enhance beta cyclin; on the other hand, when caffeine was administered in drinking water prior to UVB exposure, it inhibited UVB-induced phosphorylation of Chk1 and interfered with U…”
BackgroundResultCaffeine Abolishes the Ultraviolet-Induced REV3 Translesion Replication Pathway in Mouse Cells
Takezawa, J., Aiba, N., Kajiwara, K., & Yamada, K. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12128513 · Cited by 7 · see citing works
“[46] used a cell-permeable analog of cAMP and observed no caffeine-like effects in UVB-irradiated human keratinocytes.”
BackgroundPaiva, M. L., Yumeen, S., Kahn, B. J., Nan, H., Cho, E., Saliba, E., & Qureshi, A. (2023) · The Yale Journal of Biology and Medicine · doi:10.59249/evko3455 · Cited by 6 · see citing works
Elkoshi, N., Parikh, S., Malcov, H., Parikh, R., Manich, P., Netti, F., Maliah, A., Elkoshi, H., Haj, M., Rippin, I., et al. (2023) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2023.03.1686 · Cited by 6 · see citing works
Han, W., & He, Y. (2012) · Royal Society of Chemistry eBooks · doi:10.1039/9781849733670-00382 · Cited by 6 · see citing works
Vogel, S., & Herzinger, T. (2013) · Photodermatology Photoimmunology & Photomedicine · doi:10.1111/phpp.12071 · Cited by 5 · see citing works
“Our data that Atm was not involved in UVB signaling agree well with prior studies (37).”
ResultThe Influence of Dietary Factors on Melanoma Development and Progression: A Comprehensive Review
Watson, A. E., & Yusuf, N. (2025) · Nutrients · doi:10.3390/nu17111891 · Cited by 6 · see citing works
“Experimental studies have demonstrated that caffeine can enhance UV-induced apoptosis in keratinocytes, thereby facilitating the removal of damaged cells and reducing the likelihood of malignant transformation [51].”
Latosińska, M., & Latosińska, J. N. (2017) · InTech eBooks · doi:10.5772/intechopen.69693 · Cited by 5 · see citing works
Antioxidative mechanisms of sea buckthorn fruit extract in mouse embryonic fibroblast cells
Lim, S.-R., Go, E.-B., Go, G., Shin, H., & Sung, J. (2013) · Food Science and Biotechnology · doi:10.1007/s10068-013-0067-z · Cited by 4 · see citing works
A genome-wide analysis of gene–caffeine consumption interaction on basal cell carcinoma
Li, X., Cornelis, M. C., Liang, L., Song, F., Vivo, I. D., Giovannucci, E. L., Tang, J. Y., & Han, J. (2016) · Carcinogenesis · doi:10.1093/carcin/bgw107 · Cited by 3 · see citing works
(2013) · Digital Commons - East Tennessee State University (East Tennessee State University) · Cited by 3 · see citing works
Cosmeceutical Treatment of the Aging Face
Linder, J. (2011) · Springer eBooks · doi:10.1007/978-3-642-20113-4_8 · Cited by 3 · see citing works
Mendes, I. C., Bertoldo, W. D. R., Miranda-Junior, A. S., de Assis, A. V., Repolês, B. M., Ferreira, W. R. R., Chame, D. F., Souza, D. D. L., Pavani, R., Macedo, A. M., et al. (2024) · DNA repair · doi:10.1016/j.dnarep.2024.103726 · Cited by 2 · see citing works
Gesundheitsfördernde Wirkung von Koffein
Beiglböck, W. (2016) · Springer eBooks · doi:10.1007/978-3-662-49564-3_5 · Cited by 2 · see citing works
Cutaneous Applications of Caffeine
Hui, A. M., Jagdeo, J. R., Brody, N., & Rupani, R. (2015) · CRC Press eBooks · doi:10.1201/b18895-3 · Cited by 3 · see citing works
Zhang, X., Wang, J., Kang, J., Li, J., Li, J., Guo, C., Hao, Z., & Liu, D. (2026) · Chemical Research in Chinese Universities · doi:10.1007/s40242-026-6027-y · Cited by 1 · see citing works
Mashayekhi‐Sardoo, H., Aftabi, K., Azami, A., Rahimi, V. B., & Askari, V. R. (2025) · Toxicology Mechanisms and Methods · doi:10.1080/15376516.2025.2564124 · Cited by 3 · see citing works
“It concluded that caffeine via the ATR-Chk1 pathway and inhibition of ATR or Chk1 recovered the UV damage (Heffernan et al. 2009).”
Nguyen, T. N., Winkler, C., Ginster, S., Claudinot, S., Michalik, L., & Jafari, P. (2024) · The FASEB Journal · doi:10.1096/fj.202401950r · Cited by 2 · see citing works
Nguyen, T. N., Cherepakhin, O. S., Eng, D. K., & Kawasumi, M. (2023) · medRxiv · doi:10.1101/2023.08.07.23293443 · Cited by 1 · see citing works
Self-citationReply to: “Coffee and skin—Considerations beyond the caffeine perspective”
Oh, C. C., & Koh, W. (2019) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2019.10.021 · Cited by 1 · see citing works
Xeroderma Pigmentosum and the DNA Damage Response to Ultraviolet Light
Cleaver, J. E. (2016) · Springer eBooks · doi:10.1007/978-1-59745-458-2_24 · Cited by 1 · see citing works
Targeting Myc-driven tumours - BETing on ATR
Muralidharan, S. V. (2016) · Cited by 1 · see citing works
Basal Cell Carcinoma: Molecular and Pathological Features
Franco, R., Anniciello, A. M., Botti, G., Caraglia, M., & Luce, A. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7357-2_5 · Cited by 1 · see citing works
Song, A., Wu, J. G., Whitaker, E. E., et al. (2012) · Journal of Cancer Therapy · doi:10.4236/jct.2012.35072 · Cited by 1 · see citing works
“light B (UVB) damaged keratinocytes [38].”
Sartika, D., Patappari, A., & Syarif, A. (2021) · Jurnal Abdimas Indonesia · doi:10.53769/jai.v1i4.138
Mutations de la voie ATR-CHK1, réponse au stress réplicatif et cancer
Egger, T. (2018) · theses.fr (ABES) · doi:10.70675/eb51eb1ezc51dz4737zaf38z954d1a68dbea
Cutaneous Applications of Caffeine
Hui, A. M., Jagdeo, J. R., Brody, N., & Rupani, R. (2015) · CRC Press eBooks · doi:10.1201/b18895-5
Vessoni, A. T. (2015) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2015.tde-06102015-200543
Characterisation of UVA-induced DNA damage responses in human skin cells
Conmy, S. A. (2013) · Arrow@dit (Dublin Institute of Technology) · doi:10.13025/16394
In vitro models for investigating keratinocyte responses to ultraviolet B radiation
Fernandez, T. L. (2013)
Koffein - Wirkmechanismen und kosmetische Verwendung
Herman, A., & Herman, A. P. (2013) · Kompass Dermatologie · doi:10.1159/000354286
The spindle assembly checkpoint as a drug target - Novel small-molecule inhibitors of Aurora kinases
Salmela, A.-L. (2012) · UTUPub (University of Turku)
Han, W., & He, Y. (2012) · Royal Society of Chemistry eBooks · doi:10.1039/9781849734752-00382
Caffeine as a Photoprotective Agent
Elmets, C. A. (2009) · Journal watch · doi:10.1056/jd200903060000001
- Authors
- Heffernan, T. P., Kawasumi, M., Blasina, A., Anderes, K., Conney, A. H., & Nghiem, P.
- Affiliations
- Harvard University (US)
- Pfizer (United States) (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Nghiem, Paul
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 129
- Issue
- 7
- Pages
- 1805-1815
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC2829385
- OpenAlex
- W2117733329
- Semantic Scholar
- 008c2a1d876038b18e442a07fd69b1a59277c57f
- Cited by
- 95
- References
- 51
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 9 · 2018: 3 · 2017: 2 · 2016: 8 · 2015: 8 · 2014: 6 · 2013: 12 · 2012: 11
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Massachusetts General Hospital
- National Institutes of Health
- National Cancer Institute (R01CA114442)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR049832, K02AR050993)
- Topics
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- caffeine, UVB-induced apoptosis, ATR-Chk1 pathway, ATR, Chk1, keratinocytes, UV damage, skin cancer prevention, p53-independent apoptosis, ataxia telangiectasia, cyclic AMP, DNA damage response
- MeSH terms
- Checkpoint Kinase 1, Epidermal Cells, Adult, Aged, Caffeine, Cells, Cultured, DNA-Binding Proteins, Female, Humans, Phosphodiesterase Inhibitors, Phosphorylation, Protein Kinases, Ultraviolet Rays, Keratinocytes, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, RNA, Small Interfering, Ataxia Telangiectasia Mutated Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read under definition version 3 (extract-v3) on 2026-09-28.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
