AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields)
Open accessAbstract
Tumor Treating Fields (TTFields), an approved treatment modality for glioblastoma, are delivered via non-invasive application of low-intensity, intermediate-frequency, alternating electric fields. TTFields application leads to abnormal mitosis, aneuploidy, and increased cell granularity, which are often associated with enhancement of autophagy. In this work, we evaluated whether TTFields effected the regulation of autophagy in glioma cells. We found that autophagy is upregulated in glioma cells treated with TTFields as demonstrated by immunoblot analysis of the lipidated microtubule-associated protein light chain 3 (LC3-II). Fluorescence and transmission electron microscopy demonstrated the presence of LC3 puncta and typical autophagosome-like structures in TTFields-treated cells. Utilizing time-lapse microscopy, we found that the significant increase in the formation of LC3 puncta was specific to cells that divided during TTFields application. Evaluation of selected cell stress parameters revealed an increase in the expression of the endoplasmic reticulum (ER) stress marker GRP78 and decreased intracellular ATP levels, both of which are indicative of increased proteotoxic stress. Pathway analysis demonstrated that TTFields-induced upregulation of autophagy is dependent on AMP-activated protein kinase (AMPK) activation. Depletion of AMPK or autophagy-related protein 7 (ATG7) inhibited the upregulation of autophagy in response to TTFields, as well as sensitized cells to the treatment, suggesting that cancer cells utilize autophagy as a resistance mechanism to TTFields. Combining TTFields with the autophagy inhibitor chloroquine (CQ) resulted in a significant dose-dependent reduction in cell growth compared with either TTFields or CQ alone. These results suggest that dividing cells upregulate autophagy in response to aneuploidy and ER stress induced by TTFields, and that AMPK serves as a key regulator of this process.
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Written from the paper’s full text.
TL;DR
TTFields upregulate autophagy in glioma cells, especially in daughter cells that divide during treatment, via AMPK activation downstream of aneuploidy/ER stress and low ATP. This autophagy acts as a survival/resistance mechanism, and inhibiting it genetically or with chloroquine sensitizes glioma cells to TTFields.
Key findings
- TTFields increased cellular granularity across mesothelioma, glioma, lung, and pancreatic cancer cell lines and enlarged the acidic lysosomal pool; in U-87 MG and A172 glioma cells, TTFields increased LC3-II in a treatment-duration-dependent manner, with autophagosome-like and autolysosome structures on EM and increased LC3 staining in F98 rat gliomas in vivo.
- Autophagy induction was specific to dividing cells: LC3-GFP puncta increased in 51% of TTFields-treated cells vs 17% of untreated cells, and among cells that divided, 60% vs 16% showed increased LC3-GFP; mitotic index was 60% vs 73%, and mitosis duration was 1.5 h vs 1 h (p < 0.05).
- TTFields increased GRP78 and reduced intracellular ATP by 18% (about 1.2 vs 1.5 nmol per 0.2 × 10^6 cells), activated AMPK/ULK1, and required AMPK for autophagy: siAMPK reduced AMPK protein by 80% and abrogated LC3-II upregulation; siAMPK cells showed 47% vs 32% reduction in cell number versus siVector.
- Autophagy inhibition enhanced TTFields efficacy: shATG7 reduced cell numbers to 36% vs 64% in U-87 MG and 46% vs 62% in A172; TTFields plus low-dose CQ (3 µM) increased apoptosis to 75%, whereas CQ monotherapy increased apoptosis by 25% in A172 and 8% in U-87 MG.
Methods
- Glioma and other cancer cell lines were treated with TTFields using the inovitro system at optimal frequencies (150 or 200 kHz) and 1.75 V/cm RMS; assays included flow cytometry, LysoTracker staining, immunoblotting, immunocytochemistry, electron microscopy, ATP measurement, siRNA-mediated AMPK knockdown, shATG7 lentiviral knockdown, time-lapse microscopy of LC3-GFP, and F98 rat intracranial glioma immunohistochemistry.
- Statistical analysis used means ± SE, two-tailed Student’s t-test, and χ² analysis, with P < 0.05 considered significant; experiments were repeated at least three times with similar results.
Limitations
- The paper states that it did not examine whether TTFields-induced genotoxic stress pathways such as ATM or PARP1 activate AMPK/autophagy, and says future studies are needed.
- The paper states that CQ can have autophagy-independent effects, including Golgi and endo-lysosomal disorganization, so some enhanced efficacy of TTFields plus CQ may be unrelated to autophagy inhibition.
- Evident from the text: the mechanistic autophagy/AMPK and CQ combination experiments are largely in glioma cell lines, while in vivo evidence is limited to LC3 staining in F98 rat tumors without survival or tumor-growth outcomes.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 27 cited sources checked · 0 supported · 0 flagged
- Findingown data
TTFields application is associated with increased autophagy in F98 glioma tumors in rats.
“Application of TTFields was associated with noticeable increase in autophagy (Fig. 2b, c).”
Quote in the paperSubstantial claim - Findingown data
The mitotic index in TTFields-treated cells is lower than in control cells.
“We found that the mitotic index in TTFields-treated cells was somewhat lower than in control group (60% and 73% of cell population, respectively)”
Quote in the paperNot a substantial claim - Findingown data
Addition of CQ increases LC3-II levels in TTFields-treated cells relative to control.
“The addition of CQ, which prevents LC3-II degradation and release back to the cytoplasm, resulted in a significant increase in the LC3-II levels in cells treated with TTFields relative to control cells, as shown by immunoblotting (Fig. 3b, Supplementary Figure 1), immunofluorescent staining for quantification of LC3 puncta (Fig. 3c), as well as autophagic vacuoles accumulation using EM (supplement”
Quote in the paperSubstantial claim - Findingown data
Upregulation of LC3-GFP signal is detected in cells exhibiting visible signs of abnormal mitosis such as polyploid nucleus following slippage events.
“Upregulation in LC3-GFP signal was detected in cells that exhibited visible signs of abnormal mitosis such as polyploid nucleus following slippage events (Fig. 4c, white arrow).”
Quote in the paperSubstantial claim - Findingown data
TTFields application does not perturb LC3 and LAMP1 colocalization.
“Unlike vinblastine, a known inhibitor of autophagosome trafficking, which led to dispersed localization of the two markers, TTFields application did not perturb LC3 and LAMP1 colocalization (Fig. 3d).”
Quote in the paperSubstantial claim
- Findingown data
Autophagy is upregulated in glioma cells treated with TTFields, as shown by increased LC3-II on immunoblot.
“We found that autophagy is upregulated in glioma cells treated with TTFields as demonstrated by immunoblot analysis of the lipidated microtubule-associated protein light chain 3 (LC3-II).”
- Also stated in: § TTFields increase autophagosome formation and autophagic flux · plain
“Immunoblot assay revealed that LC3-II signal increased after TTFields application, and that this increase in autophagosome formation was dependent on treatment duration (Fig. 2a).”
Quote in the paperSubstantial claim - Also stated in: § TTFields increase autophagosome formation and autophagic flux · plain
- Findingown data
A robust increase in LC3-GFP puncta fluorescence occurs in 51% of TTFields-treated cells versus 17% of untreated cells.
“A robust increase in LC3-GFP puncta fluorescence was revealed in 51% of TTFields-treated cells relative to 17% in untreated cells (Fig. 4a, b).”
Quote in the paperSubstantial claim - Findingown data
The significant increase in formation of LC3 puncta is specific to cells that divided during TTFields application.
“Utilizing time-lapse microscopy, we found that the significant increase in the formation of LC3 puncta was specific to cells that divided during TTFields application.”
- Also stated in: § Stress response in daughter cells produced under TTFields application upregulate autophagy · plain
“Most of the cells that divided during TTFields application showed increased LC3-GFP puncta (60%) relative to 16% of the dividing cells in the untreated culture (Fig. 4d, left).”
- Also stated in: § Discussion · boosted
“We exploited single-cell analysis to show for the first time that TTFields application specifically triggers autophagy in the progeny cells that divided during treatment.”
Quote in the paperSubstantial claim - Also stated in: § Stress response in daughter cells produced under TTFields application upregulate autophagy · plain
- Findingown data
Increased LC3-GFP signal is detected in cells that completed cytokinesis but whose daughter cells showed abnormal morphology.
“An increased LC3-GFP signal was also detected in cells that had completed cytokinesis, but where the resulting daughter cells showed abnormal morphology (Fig. 4c, blue arrowhead).”
Quote in the paperNot a substantial claim - Findingown data
The duration of mitosis is longer in TTFields-treated cells than in control cells.
“and that the duration of mitosis was longer in treated cells than in control cells (1.5 h vs. 1 h, respectively, p < 0.05) (Supplementary Figure 3).”
Quote in the paperNot a substantial claim - Findingown data
The percentage of cells that did not undergo mitosis but showed increased LC3-GFP signal is similar in control and TTFields groups.
“Percentage of cells that did not undergo mitosis, but showed increased LC3-GFP signal, was similar in control and TTFields group (Fig. 4d right).”
Quote in the paperSubstantial claim - Findingown data
TTFields-treated cells contain LC3 puncta and autophagosome-like structures on fluorescence and electron microscopy.
“Fluorescence and transmission electron microscopy demonstrated the presence of LC3 puncta and typical autophagosome-like structures in TTFields-treated cells.”
- Also stated in: § TTFields increase autophagosome formation and autophagic flux · hedged
“Electron microscopy (EM) observation of ultra-structures revealed membrane-bound vesicles containing cytosolic materials or organelles, and the presence of degradative autophagic vacuoles containing partially degraded material, which was more abundant following TTFields application, indicating the existence of autophagic structures and an effective fusion process (Fig. 3a; blue and green arrows).”
Quote in the paperSubstantial claim - Also stated in: § TTFields increase autophagosome formation and autophagic flux · hedged
- Findingown data
Combination of TTFields with CQ resulted in decreased cell viability in a dose-dependent manner.
“In our study, combination of TTFields with CQ resulted in decreased cell viability in a dose-dependent manner.”
Quote in the paperSubstantial claim - Findingown data
Treated siAMPK cells demonstrate elevated levels of cleaved caspase-3.
“The treated siAMPK cells demonstrated elevated levels of cleaved caspase-3 as seen by immunofluorescent staining (Fig. 5f).”
Quote in the paperSubstantial claim - Findingown data
TTFields treatment leads to sequential ULK1 activation indicated by Ser 317 phosphorylation.
“A sequential ULK1 activation indicated by Ser 317 phosphorylation (AMPK-specific site) was also noted (Fig. 5c, Supplementary Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
TTFields treatment increases GRP78 protein levels in A172 and U-87 MG cells.
“We detected increased levels of GRP78 protein, a common marker of the endoplasmic reticulum unfolded protein response, in both A172 and U-87 MG cells treated with TTFields (Fig. 5a).”
Quote in the paperNot a substantial claim - Findingown data
Immunofluorescent staining reveals reduced prevalence of LC3 puncta in siAMPK-transfected cells relative to sham vector following 48 h TTFields.
“Further validation using immunofluorescent staining revealed reduced prevalence of LC3 puncta in siAMPK-transfected cells relative to cells transfected with sham vector following 48 h of TTFields application (Fig. 5d right panel).”
Quote in the paperSubstantial claim - Findingown data
In siAMPK cells, no changes in LC3-II protein level are observed even after addition of CQ.
“No changes in LC3-II protein level were observed even after the addition of CQ.”
Quote in the paperSubstantial claim - Findingown data
TTFields application for 48 h leads to a significant reduction in number of siAMPK cells relative to sham vector transfected cells (47% vs 32% reduction).
“TTFields application for 48 h led to a significant reduction in the number of siAMPK cells relative to sham vector transfected cells (47% and 32% reduction in siAMPK and siVector, respectively) (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Silencing AMPK in U-87 MG cells reduces AMPK protein levels by 80%.
“Silencing of AMPK in U-87 MG cells, using small interfering RNAs (siRNAs; siAMPK) resulted in 80% reduction in AMPK protein levels”
Quote in the paperSubstantial claim - Findingown data
TTFields treatment increases phosphorylated AMPK levels in U-87 MG and A172 glioma cell lines.
“Using immunoblot assay, we observed significantly elevated levels of phosphorylated AMPK in U-87 MG and A172 glioma cell lines treated with TTFields at the indicated time points (Fig. 5c, Supplementary Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Blocking autophagy induced by TTFields by using either genetic or pharmacologic approaches results in increased treatment efficacy.
“Specifically, our results demonstrate that blocking autophagy induced by TTFields by using either genetic or pharmacologic approaches, results in increased treatment efficacy.”
Quote in the paperSubstantial claim - Findingown data
Intracellular ATP levels are reduced by 18% in U-87 MG cells treated with TTFields relative to untreated.
“In addition, intracellular ATP levels were found to be reduced by 18% (p < 0.05) in treated cells (~1.2 nmol for 0.2 × 106 cells) relative to untreated (~1.5 nmol for 0.2 × 106 cells) (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
Inhibition of autophagy by shATG7 leads to a significant decrease in cell numbers following 72 h TTFields relative to sham vector.
“Inhibition of autophagy led to a significant decrease in cell numbers following 72 h of TTFields application relative to cells expressing sham vector (36% vs. 64% of cell reduction in shVector and shATG7 cells, respectively, in U-87 MG and 46% vs. 62% in A172) (Fig. 6a, Supplementary Figure 5).”
Quote in the paperSubstantial claim - Findingown data
TTFields application leads to larger acidic lysosomal pool in treated cells.
“This can potentially be attributed to lysosomes accumulation, which was confirmed by fluorescent microscopy of LysoTracker-stained cells, which demonstrated larger acidic lysosomal pool in TTFields-treated cells (Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
Combining TTFields with CQ results in a significant reduction in cell numbers.
“We found that the combination treatment resulted in a significant reduction in cell numbers.”
Quote in the paperSubstantial claim - Findingown data
Silencing AMPK abrogates the increase in LC3-II levels in response to 48 h TTFields application.
“and abrogated the increase in LC3-II levels in response to 48 h TTFields application (Fig. 5d).”
Quote in the paperSubstantial claim - Findingnone given
Upregulation of autophagy by TTFields is restricted to dividing cells.
“Our findings demonstrate that the upregulation of autophagy by TTFields is restricted to dividing cells, which may explain the relatively lack of safety issues with this modality.”
Quote in the paperSubstantial claim - Findingown data
Presence of low concentration of CQ, which has no effect on cell number as a monotherapy, resulted in high levels of apoptosis when combined with TTFields.
“Moreover, the presence of low concentration of CQ, which has no effect on cell number as a monotherapy, resulted in high levels of apoptosis when combined with TTFields (Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
Sham vector-transfected cells show elevated LC3-II after TTFields similar to wild-type U-87 MG cells.
“Cells transfected with sham vector demonstrated elevated levels of LC3-II after treatment with TTFields similar to U-87 MG wild-type cells (Fig. 5d left panel).”
Quote in the paperNot a substantial claim - Premisecitation
Increased cellular granularity is typically associated with senescence and autophagy.
“Increased cellular granularity is typically associated with senescence and autophagy15,16.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [15] Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26, 9220–9231 (2006). source
Not checked in the free run.
- cites [16] Gosselin, K. et al. Senescent keratinocytes die by autophagic programmed cell death. Am. J. Pathol. 174, 423–435 (2009). source
Not checked in the free run.
- Premisecitation
TTFields induce autophagy in glioma cell lines.
“A recent study supports this hypothesis by providing evidence that TTFields induce autophagy in glioma cell lines17.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Silginer, M., Weller, M., Stupp, R. & Roth, P. Biological activity of tumor-treating fields in preclinical glioma models. Cell Death Dis. 8, e2753 (2017). source
Not checked in the free run.
- Interpretationown data
Induction of autophagy following TTFields treatment is a consequence of aberrant mitosis.
“We conclude that the induction of autophagy following TTFields treatment is a consequence of aberrant mitosis.”
Quote in the paperSubstantial claim - Interpretationown data
Inhibition of the AMPK pathway renders cells more susceptible to TTFields treatment.
“and that inhibition of this pathway rendered the cells more susceptible to treatment.”
Quote in the paperSubstantial claim - Interpretationown data
Our data indicate a similar resistance pattern of cells utilizing autophagy to evade lethal effects, despite TTFields differing in mode of action from chemo and radiotherapy.
“Although TTFields differ significantly in their mode of action from chemo and radiotherapy, our data indicate a similar resistance pattern of cells utilizing autophagy to evade lethal effects.”
Quote in the paperSubstantial claim - Interpretationown data
TTFields-upregulated autophagy is mediated through the AMPK pathway.
“Collectively, these results indicate that TTFields’ upregulated autophagy is mediated through the AMPK pathway, and that inhibition of this pathway rendered the cells more susceptible to treatment.”
Quote in the paperSubstantial claim - Interpretationown data
Inhibition of autophagy sensitizes glioma cells to TTFields treatment.
“These results demonstrate that the inhibition of autophagy sensitizes glioma cells to TTFields treatment.”
Quote in the paperSubstantial claim - Interpretationown data
Glioma cells upregulate autophagy as a resistance mechanism to TTFields.
“Overall, these findings suggest that glioma cells upregulate autophagy as a resistance mechanism to TTFields, and that pharmacological inhibition of autophagy circumvents this resistance and enhances the anti-mitotic effects of TTFields.”
- Also stated in: § Discussion · boosted
“In this study, we demonstrate that daughter cells surviving TTFields application upregulate autophagy in response to proteotoxic stress, thereby promoting resistance to treatment (Fig. 7).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Premisecitation
Silginer et al. demonstrated that concomitant use of 3-MA during TTFields application results in higher cell viability.
“Interestingly, a recent study by Silginer et al.17 demonstrated that the concomitant use of 3-Methyladenine (3-MA; early-stage inhibitor of autophagy) during TTFields application result in higher cell viability.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Silginer, M., Weller, M., Stupp, R. & Roth, P. Biological activity of tumor-treating fields in preclinical glioma models. Cell Death Dis. 8, e2753 (2017). source
Not checked in the free run.
- Interpretationown data
TTFields-induced autophagy is dependent on AMPK activation.
“Our data indicate that TTFields-induced autophagy is mediated and dependent on AMPK activity, which is in line with the observed proteotoxic stress response and reduced ATP intracellular levels, as AMPK is activated by low-energy status.”
Quote in the paperSubstantial claim - Premisecitation
Inhibition at late stages in autophagy (e.g., using bafilomycin or CQ) led to enhanced efficacy of the same treatment as reflected by increased cytotoxic effect.
“On the other hand, inhibition at late stages in autophagy (e.g., using bafilomycin or CQ) led to enhanced efficacy of the same treatment as reflected by increased cytotoxic effect, suggesting that accumulation of autolysosomes is necessary for cell death induction45,46.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [45] Shingu, T. et al. Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int. J. Cancer 124, 1060–1071 (2009). source
Not checked in the free run.
- cites [46] Verschooten, L. et al. Autophagy inhibitor chloroquine enhanced the cell death inducing effect of the flavonoid luteolin in metastatic squamous cell carcinoma cells. PLoS One 7, e48264 (2012). source
Not checked in the free run.
- Interpretationreasoning
Autophagy is triggered via AMPK activation in response to aneuploid status following cell division under TTFields application.
“Therefore, we propose that autophagy is triggered via AMPK activation in response to aneuploid status following cell division under TTFields application (Fig. 7).”
Quote in the paperSubstantial claim - Interpretationown data
The restriction of TTFields-induced autophagy upregulation to dividing cells may explain the relative lack of safety issues with TTFields.
“Our findings demonstrate that the upregulation of autophagy by TTFields is restricted to dividing cells, which may explain the relatively lack of safety issues with this modality.”
Quote in the paperSubstantial claim- Rests on an assumption: Effective TTFields intensities are present not just in the tumor but also in the surrounding tissues and may potentially affect normal bystander cells.
- Rests on an assumption: Both preclinical and clinical evidence did not reveal adverse events in normal tissues.
- Interpretationown data
The results indicate increased treatment efficacy for the combined treatment of TTFields with CQ.
“These results indicate increased treatment efficacy for the combined treatment and provide strong rationale for additional in-vivo studies.”
Quote in the paperSubstantial claim - Premisecitation
In treatment regimens utilizing cytotoxic drugs combined with agents that inhibit autophagy at an early stage, the cytotoxic effect was hindered.
“It has been reported that in treatment regimens utilizing cytotoxic drugs combined with agents that inhibit autophagy at an early stage, the cytotoxic effect was hindered.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [45] Shingu, T. et al. Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int. J. Cancer 124, 1060–1071 (2009). source
Not checked in the free run.
- cites [46] Verschooten, L. et al. Autophagy inhibitor chloroquine enhanced the cell death inducing effect of the flavonoid luteolin in metastatic squamous cell carcinoma cells. PLoS One 7, e48264 (2012). source
Not checked in the free run.
- Interpretationown data
Changes in cellular granularity following TTFields can potentially be attributed to lysosome accumulation.
“This can potentially be attributed to lysosomes accumulation, which was confirmed by fluorescent microscopy of LysoTracker-stained cells, which demonstrated larger acidic lysosomal pool in TTFields-treated cells (Fig. 1c).”
Quote in the paperNot a substantial claim - Premisecitation
CQ can also inflict severe disorganization of the Golgi and endo-lysosomal systems.
“Although CQ is primarily acknowledged as blocker of lysosomal degradation, a recent study by Mauthe et al.47 demonstrated that CQ can also inflict severe disorganization of the Golgi and endo-lysosomal systems.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Mauthe, M. et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 14, 1435–1455 (2018). source
Not checked in the free run.
- Interpretationcitation
Some elements of the enhanced treatment efficacy of the combined treatment with CQ may be attributed to other autophagy-unrelated cellular alterations.
“Therefore, it is imperative to also acknowledge the autophagy-independent effects of CQ and the possibility that some elements of the enhanced treatment efficacy of the combined treatment with CQ may be attributed to other autophagy-unrelated cellular alterations.”
Quote in the paperNot a substantial claim
- The quote only partly states this claim. 1
- May combine two claims. 10
- Classified as probably not a substantial claim. 22
The quote only partly states this claim.
Findingown dataTTFields application increases cellular granularity in various cancer cell lines.
“In all cell lines tested, TTFields application resulted in changes in cellular granularity (Fig. 1a, b)25.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Marina, O. C., Sanders, C. K. & Mourant, J. R. Correlating light scattering with internal cellular structures. Biomed. Opt. Express 3, 296–312 (2012). source
Not checked in the free run.
May combine two claims.
Findingown dataFlow cytometry reveals higher levels of apoptosis (75%) in cells treated with TTFields plus low dose CQ (3 μM), whereas CQ monotherapy results in only 25% increase in apoptosis in A172 cells and 8% in U-87 MG cells.
“Flow cytometry analysis revealed higher levels of apoptosis (75%) in cells treated with TTFields in combination with low dose CQ (3 µM), whereas CQ monotherapy resulted in only 25% increase in apoptosis in A172 cells and 8% in U-87 MG cells (Fig. 6c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataImprovement in efficacy with TTFields plus CQ is observed even at low CQ concentrations (3 μM), whereas CQ monotherapy has no effect on cell counts.
“Of note, this improvement in efficacy was observed even at low CQ concentrations (3 µM), whereas CQ monotherapy had no effect on cell counts (Fig. 6b).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTTFields application increases autophagic flux in glioma cell lines without substantially affecting fusion degradation steps.
“Taken together, these results demonstrate that TTFields application lead to an increase in the autophagic flux in glioma cell lines with no substantial influence on the fusion degradation steps.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTTFields application leads to abnormal mitosis and aneuploidy in cancer cells.
“TTFields application leads to abnormal mitosis, aneuploidy, and increased cell granularity, which are often associated with enhancement of autophagy.”
- Also stated in: § Stress response in daughter cells produced under TTFields application upregulate autophagy · plain
“Abnormal mitosis following TTFields application results in different cell fates including the formation of aneuploid daughter cells7,8.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] Voloshin, T. et al. Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo. Int. J. Cancer 139, 2850–2858 (2016). source
Not checked in the free run.
- cites [8] Giladi, M. et al. Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci. Rep. 5, 18046 (2015). source
Not checked in the free run.
- Also stated in: § Stress response in daughter cells produced under TTFields application upregulate autophagy · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPARP1 is associated with elevated AMP levels that activate AMPK.
“Another example is the DNA damage repair enzyme PARP1, which is associated with elevated AMP levels that activate AMPK37.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Rodriguez-Vargas, J. M. et al. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. Cell Res. 22, 1181–1198 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAccumulation of autolysosomes is necessary for cell death induction.
“On the other hand, inhibition at late stages in autophagy (e.g., using bafilomycin or CQ) led to enhanced efficacy of the same treatment as reflected by increased cytotoxic effect, suggesting that accumulation of autolysosomes is necessary for cell death induction45,46.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] Shingu, T. et al. Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int. J. Cancer 124, 1060–1071 (2009). source
Not checked in the free run.
- cites [46] Verschooten, L. et al. Autophagy inhibitor chloroquine enhanced the cell death inducing effect of the flavonoid luteolin in metastatic squamous cell carcinoma cells. PLoS One 7, e48264 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA preclinical glioma model showed that autophagy upregulation in response to temozolomide confers resistance to treatment.
“A preclinical glioma model showed that autophagy upregulation in response to temozolomide confers resistance to treatment42.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Jawhari, S., Ratinaud, M. H. & Verdier, M. Glioblastoma, hypoxia and autophagy: a survival-prone ‘menage-a-trois’. Cell Death Dis. 7, e2434 (2016). source
Not checked in the free run.
May combine two claims.
Interpretationown dataPharmacological inhibition of autophagy circumvents resistance and enhances anti-mitotic effects of TTFields.
“and that pharmacological inhibition of autophagy circumvents this resistance and enhances the anti-mitotic effects of TTFields.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were repeated at least three times with similar results.
“All experiments were repeated at least three times with similar results.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTTFields can potentially induce replication stress and reduction of BRCA1 pathway proteins, eventually leading to genotoxic stress, as shown by Karanam et al.
“It is noteworthy that Karanam et al.11 have recently shown that TTFields can potentially induce replication stress and reduction of BRCA1 pathway proteins, eventually leading to genotoxic stress.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Karanam, N. K. et al. Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis. 8, e2711 (2017). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationInduction of autophagy in normal tissue may exert a detrimental effect and lead to autophagic cell death.
“Induction of autophagy in normal tissue may exert a detrimental effect and lead to autophagic cell death38,39.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [38] Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011). source
Not checked in the free run.
- cites [39] Zhuang, H., Ali, K., Ardu, S., Tredwin, C. & Hu, B. Autophagy in dental tissues: a double-edged sword. Cell Death Dis. 7, e2192 (2016). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCombination of CQ with 17-allylamino-17-demethoxy-geldanamycin and 5-aminoimidazole-4-carboxamide riboside promotes proteotoxic and metabolic stress leading to induction of apoptosis exclusively in aneuploid cells.
“The combination of CQ with two additional drugs, 17-allylamino-17-demethoxy-geldanamycin and 5-aminoimidazole-4-carboxamide riboside, had been shown to promote proteotoxic and metabolic stress leading to the induction of apoptosis exclusively in aneuploid cells27.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Tang, Y. C., Williams, B. R., Siegel, J. J. & Amon, A. Identification of aneuploidy-selective antiproliferation compounds. Cell 144, 499–512 (2011). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThree different areas of similar size from each image were chosen in a blinded manner to be analyzed.
“Three different areas of similar size from each image were chosen in a blinded manner to be analyzed by ImagJ software.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCount of autophagic vacuoles was performed manually in a blinded manner.
“Count of autophagic vacuoles was performed manually in a blinded manner.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenControl rats were treated with sham electrodes geometrically matched to the TTFields group.
“Control rats were treated by means of sham electrodes, which were geometrically matched to the TTFields group.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation3-MA blocks class I and class III PI3K activity, exhibiting dual activity that could lead to either inhibition or upregulation of autophagy.
“3-MA is known to block class I and class III PI3K activity, thus exhibiting dual activity that could lead to either inhibition or upregulation of autophagy44.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Wu, Y. T. et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J. Biol. Chem. 285, 10850–10861 (2010). source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductreasoningSham heat electrodes produced equal temperature changes to those produced by field electrodes.
“The Sham heat electrodes produced equal temperature changes to those produced by the field electrodes by means of a heating resistor incorporated within them.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningIn addition to aneuploidy, AMPK-dependent induction of autophagy can also be potentially triggered by genotoxic stress.
“Therefore, in addition to aneuploidy, AMPK-dependent induction of autophagy can also be potentially triggered by such genotoxic stress.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCleaved caspase-3-positive cells were quantified manually in a blinded manner.
“The quantification of cleaved caspase-3-positive cells was done manually in a blinded manner.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationATM can activate AMPK, leading to induction of autophagy.
“For example, the serine/threonine kinase ATM, which is a major sensor of DNA double-strand breaks, can activate AMPK, thus leading to induction of autophagy35,36.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35] Alexander, A. et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. Natl Acad. Sci. USA 107, 4153–4158 (2010). source
Not checked in the free run.
- cites [36] Alexander, A., Kim, J. & Walker, C. L. ATM engages the TSC2/mTORC1 signaling node to regulate autophagy. Autophagy 6, 672–673 (2010). source
Not checked in the free run.
May combine two claims.
Interpretationown dataDaughter cells surviving TTFields application upregulate autophagy in response to proteotoxic stress, thereby promoting resistance to treatment.
“In this study, we demonstrate that daughter cells surviving TTFields application upregulate autophagy in response to proteotoxic stress, thereby promoting resistance to treatment (Fig. 7).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataATG7 protein levels in stable culture were validated in western blot analysis.
“ATG7 protein levels in stable culture were further validated in western blot analysis with specific anti ATG7 (rabbit monoclonal, Cell Signaling) antibody.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationTargeting a complex process such as autophagy may lead to different consequences depending on the exact stage of autophagy being targeted.
“Targeting a complex process such as autophagy may lead to different consequences depending on the exact stage of autophagy being targeted.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExtensive preclinical evidence for the involvement of autophagy in cancer cell survival has led to a rise in clinical trials evaluating autophagy inhibitors in combination with chemotherapy.
“Extensive preclinical evidence for the involvement of autophagy in cancer cell survival has led to a rise in clinical trials, which are underway to evaluate the therapeutic potential of autophagy inhibitors in combination with chemotherapy18,40,41.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [18] Towers, C. G. & Thorburn, A. Therapeutic targeting of autophagy. EBioMedicine 14, 15–23 (2016). source
Not checked in the free run.
- cites [40] Chen, S. et al. Autophagy is a therapeutic target in anticancer drug resistance. Biochim. Biophys. Acta 1806, 220–229 (2010).
Not checked in the free run.
- cites [41] Kumar, A., Singh, U. K. & Chaudhary, A. Targeting autophagy to overcome drug resistance in cancer therapy. Future Med. Chem. 7, 1535–1542 (2015). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSingle cells were followed manually by two independent investigators.
“Single cells were followed manually by two independent investigators.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMitotic events were recorded in a blinded manner.
“Mitotic events were recorded in a blinded manner.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCQ and its derivative hydroxychloroquine are currently the only clinically available drugs to inhibit autophagy.
“CQ and its derivative hydroxychloroquine, a broadly used anti-malarial agent, are currently the only clinically available drugs to inhibit autophagy43.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal studies were approved by the Novocure Internal Animal Care Committee in accordance with Technion-Israel Institute of Technology guidelines.
“All animal studies were approved by the Novocure Internal Animal Care Committee in accordance with the Technion‐Israel Institute of Technology guidelines for the care of laboratory animals.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningTTFields enhance autophagy in glioma cells as part of a cellular response to aberrant mitosis, with aneuploidy having a crucial role.
“This finding suggests that TTFields enhance autophagy in glioma cells as part of a cellular response to aberrant mitosis, with aneuploidy having a crucial role.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Senescence is not detected in cells treated with TTFields.
“As senescence was not detected in cells treated with TTFields, we hypothesized that the origin of the observed granularity may be due to the accumulation of autophagosome vesicles8.”
The paper relies on this without support.
Effective TTFields intensities are present not just in the tumor but also in the surrounding tissues and may potentially affect normal bystander cells.
“Effective TTFields intensities are present not just in the tumor but also in the surrounding tissues and may potentially affect normal bystander cells.”
The paper relies on this without support.
Both preclinical and clinical evidence did not reveal adverse events in normal tissues.
“However, both preclinical and clinical evidence did not reveal adverse events in normal tissues.”
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?
Alternating electric fields disrupt the membranes of subcellular compartments.
“For example, the application of alternating electric fields has been shown to disrupt the membranes of subcellular compartments [85] as well as the plasma membrane of human glioblastoma cells [27].”
From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
ATP treatment duration differs between figure and methods
MajorThe Fig. 5b caption says ATP was measured after 72 hours of TTFields treatment, whereas the ATP measurement method says cells were collected after 48 hours.
“Quantification of intracellular ATP levels in U-87 MG cells either left untreated or treated with TTFields for 72 h.”
“After 48 h of treatment, cells were collected and 1 × 106 cells from each sample were resuspended in ATP lysis buffer.”
ATP levels are reported for different cell counts
MinorThe results give ATP amounts per 0.2 × 10^6 cells, while the Fig. 5b caption labels the ATP concentration per 2 × 10^6 cells-a tenfold difference in the stated denominator.
“~1.2 nmol for 0.2 × 106 cells) relative to untreated (~1.5 nmol for 0.2 × 106 cells)”
“The results are presented as average ATP concentration (nmol/2 × 106 cells)”
Two-replicate result conflicts with stated minimum of three
MinorThe Fig. 5f caption reports n = 2, while the statistical analysis section says all experiments were repeated at least three times.
“(**P < 0.01, Student’s t-test, n = 2)”
“All experiments were repeated at least three times with similar results.”
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Tumour treating fields therapy for glioblastoma: current advances and future directions
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Treatment of Glioblastoma (GBM) with the Addition of Tumor-Treating Fields (TTF): A Review
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The Mechanisms of Action of Tumor Treating Fields
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Permeabilizing Cell Membranes with Electric Fields
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Tumor-Treating Fields Therapy for Pediatric Brain Tumors
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The Evidence That Brain Cancers Could Be Effectively Treated with In-Home Radiofrequency Waves
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- Authors
- Shteingauz, A., Porat, Y., Voloshin, T., Schneiderman, R. S., Munster, M., Zeevi, E., Kaynan, N., Gotlib, K., Giladi, M., Kirson, E. D., Weinberg, U., Kinzel, A., & Palti, Y.
- Corresponding author
- Giladi, Moshe
- Venue
- Cell Death & Disease
- Published
- 2018-10-19
- Volume
- 9
- Issue
- 11
- Pages
- 1074-1074
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6195570
- OpenAlex
- W2897336072
- Semantic Scholar
- 0c9028c6bb3ef5d1625b9f88285f8d67f0509e07
- Cited by
- 107
- References
- 53
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 18 · 2023: 16 · 2022: 23 · 2021: 12 · 2020: 9 · 2019: 7 · 2018: 1
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Novocure Ltd
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
- Keywords
- tumor treating fields, glioblastoma, autophagy, AMPK, ATG7, endoplasmic reticulum stress, GRP78, aneuploidy, chloroquine, tumor cell survival, LC3-II, AC electric field
- MeSH terms
- Autophagosomes, Autophagy-Related Protein 7, Endoplasmic Reticulum Chaperone BiP, Adenosine Triphosphate, Aneuploidy, Animals, Autophagy, Brain Neoplasms, Cell Survival, Electric Stimulation, Electric Stimulation Therapy, Glioblastoma, Heat-Shock Proteins, Humans, Lysosomes, Microtubule-Associated Proteins, Mitosis, Up-Regulation, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice, Rats, AMP-Activated Protein Kinases, Endoplasmic Reticulum Stress
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