The DOI matches its Crossref record; 65 of the 67 references it cites were found in a registry or an index; 35 of the 50 sources its claims cite were checked for support.
An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway
Open accessPublished version of a preprint
Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)–dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1–dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)–mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1–dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients. Significance: This study reveals that GBM cells have devised a mechanism to subvert the normal pathways for feedback inhibition of cholesterol homeostasis via EGFRvIII and PI3K-dependent activation of SREBP-1. We show that an LXR agonist causes IDOL-mediated LDLR degradation and increases expression of the ABCA1 cholesterol efflux transporter, potently promoting GBM cell death in vivo. These results suggest a role for LXR agonists in the treatment of GBM patients. Cancer Discovery; 1(5): 442–56. ©2011 AACR. Read the Commentary on this article by Moschetta, p. 381 This article is highlighted in the In This Issue feature, p. 367
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Written from the paper’s full text.
TL;DR
In GBM models and patient samples, EGFRvIII/PI3K signaling drives SREBP-1-dependent LDLR expression, creating dependence on exogenous cholesterol. The LXR agonist GW3965 degrades LDLR via IDOL and induces ABCA1-mediated efflux, promoting GBM cell death and inhibiting tumor growth in vivo.
Key findings
- EGFRvIII expression increased LDLR in U87MG and GBM39 xenografts; erlotinib suppressed LDLR, and EGFR/PI3K/Akt inhibition or SREBP-1 knockdown reduced LDLR expression.
- In 140 GBM patient samples, LDLR was detected in 85.7% of tumors, was enriched in p-EGFR-positive tumors (97%), and correlated with p-Akt and nuclear SREBP-1 (p<0.001); lapatinib treatment decreased LDLR in two patients.
- LDL depletion inhibited growth by 60% in EGFRvIII-expressing GBM cells versus half as much in parental U87 cells; GW3965 caused greater cell death in EGFRvIII cells, rescued by LDL.
- In vivo, GW3965 (40 mg/kg daily oral gavage for 12 days) inhibited U87/EGFRvIII tumor growth by 59% and increased apoptosis 25-fold; IDOL-mediated LDLR degradation was necessary but not sufficient for GW3965-induced death.
Methods
- Cell lines (U87, U87-EGFRvIII, U87-EGFR, LN229, U251, GBM39 xenografts, others) were used with immunoblot, real-time PCR, proliferation/death assays, shRNA/siRNA knockdown, and adenoviral IDOL expression.
- Xenograft studies implanted U87, U87-EGFRvIII, or GBM39 cells subcutaneously in SCID/Beige mice; GW3965 efficacy was assessed by tumor growth and TUNEL apoptosis.
- Clinical analysis used tissue microarrays from 140 GBM patients and paired pre/post-lapatinib tumor tissue from two patients; statistics included Fisher’s exact test, two-tailed t test, and ANOVA with p<0.05.
Limitations
- Stated: correlation analysis cannot prove causality; the authors cannot formally exclude that non-cholesterol LDL components contribute; no antibodies detect endogenous IDOL; future studies are needed to test other PI3K-driven cancers and mTOR regulation.
- Evident: in vivo efficacy was shown in a subcutaneous U87/EGFRvIII xenograft rather than an orthotopic GBM model, and the lapatinib clinical validation included only two patients.
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Claims the paper makes
46 Own result · 27 Own interpretation · 16 Partly supported · 4 Supported · 4 No basis given · 2 No full text of the sources · 2 Own method · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“PI3K signaling may be central to linking the common genetic perturbations of cancer, such as RTK mutations and PTEN loss, with altered metabolic processes, including the “lipogenic phenotype” common to many cancers, including GBM (13, 14, 17, 20).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Not checked — no full text of the sourcecites [13] Guo, 2009, The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis, Proc Natl Acad Sci U S A source
- Partly supportedcites [14] Guo, 2009, EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy, Sci Signal sourceExperimental — accuracy not yet measured
The Results section links EGFR–PI3K–Akt signaling to increased fatty-acid synthesis in GBM cells, and the Introduction and Discussion connect RTK activity and PTEN loss to PI3K signaling. The Discussion mentions a possible extension to other EGFR-activated cancers, but does not establish that the lipogenic phenotype is common to many cancers. The indexed passages provide section labels but no page numbers. (LLM, conf=0.83)
- Partly supportedcites [17] Heiden, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science sourceExperimental — accuracy not yet measured
“Metabolic Regulation Is a Component of the Cell Growth Machinery” links PI3K signaling to growth control and glucose metabolism. “Crunching the Numbers–What Are the Metabolic Needs of Proliferating Cells?” describes fatty-acid synthesis, but our copy does not link PI3K to a lipogenic phenotype or establish the claimed connection through RTK mutations and PTEN loss, including in GBM. The indexed passages provide no page numbers. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [20] Shaw, 2006, Ras, PI(3)K and mTOR signalling controls tumour cell growth, Nature source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, other RTKs that can be co-expressed in GBM, including some that may be upregulated after EGFR inhibitor therapies, like c-MET, PDGFR-alpha and PDGFR-beta, can also engage PI3K signaling, resulting in EGFR inhibitor resistance (12).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Partly supportedcites [12] Stommel, 2007, Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies, Science sourceExperimental — accuracy not yet measured
The paper reports co-activated MET and PDGFRs in GBM and shows that multiple RTKs can maintain PI3K signaling despite EGFR inhibition (pp. 1–2). It does not establish the citing sentence’s additional suggestion that these RTKs may be upregulated after EGFR inhibitor therapy. (LLM, conf=0.84)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Therefore, other PI3K pathway activating lesions commonly found in GBM, such as the activation of other RTKs (6, 12, 39), could also promote increased LDLR expression.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFR/PI3K/Akt signaling and nuclear SREBP-1 staining correlate with elevated LDLR expression in GBM patient samples
What the sources say
- Supportedcites [6] Cancer Genome Atlas Research Network, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature source
The Results section reports that 86% of GBM samples had a genetic event in the RTK/PI3K pathway and identifies aberrations in several RTKs, including PDGFRA and MET. The citation supports the statement that these lesions occur in GBM; the suggestion that they could increase LDLR expression is the citing authors’ own inference. (LLM, conf=0.91)
- Supportedcites [12] Stommel, 2007, Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies, Science source
The citation is attached to the activation of other RTKs in GBM, not to the citing authors’ prediction about LDLR expression. The paper reports multiple activated RTKs in primary GBMs (p. 3) and finds that combined RTK inhibition reduces PI3K signaling in glioma cells (p. 2). (LLM, conf=0.91)
- Partly supportedcites [39] Wheeler, 2010, Understanding resistance to EGFR inhibitors—impact on future treatment strategies, Nat Rev Clin Oncol sourceExperimental — accuracy not yet measured
The ‘Role of IGF-1R in resistance to EGFR inhibitors’ section reports that IGF-1R, an RTK, was upregulated in two primary GBM cell lines and sustained PI3K/AKT signaling. That supports the citation attached to activation of other RTKs, but the section does not establish that such activation is commonly found in GBM. The proposed increase in LDLR expression is the citing authors’ own inference, not the point to which this citation is attached. (LLM, conf=0.82)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We previously showed that limiting intracellular sterol availability by pharmacologically driving the LXR pathway inhibits the proliferation of rapidly dividing cell types such as lymphocytes (28).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Partly supportedcites [28] Bensinger, 2008, LXR signaling couples sterol metabolism to proliferation in the acquired immune response, Cell sourceExperimental — accuracy not yet measured
The Results report that LXR agonists block lymphocyte proliferation through ABCG1-dependent changes in intracellular sterol metabolism, and that excess mevalonate reverses the inhibition. The Discussion describes the more specific mechanism of localized sterol depletion as likely, rather than established; the claim presents that limitation of sterol availability as fact. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In pre-clinical models (Figure 1F) and in GBM patients treated with rapamycin (14, 64), we have shown that SREBP-1 activation, and consequent LDLR expression, are rapamycin resistant (Figure 1F).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Partly supportedcites [14] Guo, 2009, EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy, Sci Signal sourceExperimental — accuracy not yet measured
The Results sections on rapamycin-treated GBM patients and GBM cells report that rapamycin did not reduce nuclear SREBP-1 staining or prevent EGFR-mediated SREBP-1 cleavage. The paper discusses SREBP-1 regulation of fatty acid synthase, but the passages found do not establish that consequent LDLR expression is rapamycin resistant. Page numbers were not available in our copy. (LLM, conf=0.88)
- Could not verifycites [64] Cloughesy, 2008, Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma, PLoS Med sourceExperimental — accuracy not yet measured
The Results sections describe rapamycin treatment in GBM patients and measure mTOR activity through S6 phosphorylation, but they do not report SREBP-1 activation or LDLR expression. Searches for SREBP-1, LDLR, and their expanded names found no passage addressing whether either is rapamycin resistant. (LLM, conf=0.75)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“LXR agonists may be highly beneficial because of their ability to coordinately target two of the three aspects of cholesterol regulation (27).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Supportedcites [27] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science source
The paper’s Abstract identifies uptake, efflux and synthesis as the three contributors to cellular cholesterol levels, and says LXR promotes efflux while suppressing LDL uptake. Its concluding passage describes coordinated regulation of Idol and ABCA1, while the Abstract reports that synthetic LXR agonists protect mice against atherosclerosis. Together these support the citing sentence’s hedged statement of potential benefit. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Moreover, consistent with the enhanced dependence of EGFRvIII-bearing tumor cells on exogenous cholesterol, these cells exhibited markedly greater cell death compared to the parental U87 cell line (Figure 4, A–D).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > The LXR agonist GW3965 promotes GBM cell death in vitro with enhanced efficacy in EGFRvIII-expressing tumor cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and a 25-fold increase in GBM cell apoptosis (Figure 7, D and E).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > LXR agonist inhibits GBM tumor growth in vivo
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, this was accompanied by 59% inhibition of tumor growth (Figure 7, B and C)”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > LXR agonist inhibits GBM tumor growth in vivo
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LDLR staining was significantly enriched in tumors co-expressing p-EGFR, being detected in 97% of p-EGFR positive tumors.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFR/PI3K/Akt signaling and nuclear SREBP-1 staining correlate with elevated LDLR expression in GBM patient samples
plaincorrelationaln = 140- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 19
- It may state two separate claims as one. 28
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Cancer cells preferentially metabolize glucose by aerobic glycolysis, a phenomenon known as the Warburg effect.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Not checked — no full text of the sourcecites [16] DeBerardinis, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab source
- Supportedcites [17] Heiden, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science source
In “Proliferating Mammalian Cells Exhibit Anabolic Metabolism,” the paper says most cancer cells produce large amounts of lactate regardless of oxygen availability and calls this metabolism “aerobic glycolysis.” It also identifies this pattern as Warburg’s observation. The claim is a fair paraphrase, though the paper specifies “most” rather than all cancer cells. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [18] Kroemer, 2008, Tumor cell metabolism: cancer's Achilles' heel, Cancer Cell source
- Not checked — no full text of the sourcecites [19] Menendez, 2007, Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis, Nat Rev Cancer source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“PI3K signaling is hyperactivated in nearly 90% of GBMs, commonly as a consequence of EGFR amplification and activating mutation (EGFRvIII), and loss of the PTEN tumor suppressor protein, a negative regulator of PI3K signaling (6–8).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Partly supportedcites [6] Cancer Genome Atlas Research Network, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature sourceExperimental — accuracy not yet measured
The Results section reports that 86% of GBM samples had a genetic event in the RTK/PI3K pathway, and documents EGFR amplification, EGFRvIII, and PTEN deletions or mutations (page not provided). That supports the approximate prevalence and the named genetic alterations, but the paper does not establish that PI3K signaling was measured as hyperactivated in nearly 90% of tumors or that PTEN protein was lost in those cases. (LLM, conf=0.88)
- Partly supportedcites [7] Parsons, 2008, An integrated genomic analysis of human glioblastoma multiforme, Science sourceExperimental — accuracy not yet measured
The Integration of sequencing, copy number, and expression analyses section reports alterations in PI3K/PTEN-pathway genes in 50% of tumors and identifies EGFR and PTEN alterations in 30–40% of GBMs. It does not report PI3K signaling hyperactivation in nearly 90% of GBMs or establish EGFRvIII and PTEN protein loss as its common causes. Page numbers are unavailable in our copy. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [8] Chakravarti, 2004, The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas, J Clin Oncol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“LXRs respond to excess cellular cholesterol by promoting ABCA1- and ABCG1-dependent cholesterol efflux and by inhibiting LDLR protein expression through induction of the E3 ubiquitin ligase IDOL (27).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Supportedcites [27] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science source
The paper states that LXRs respond to cellular cholesterol excess and that LXR targets ABCA1 and ABCG1 promote cholesterol efflux. It also reports that LXR induces the E3 ubiquitin ligase Idol, which targets LDLR for degradation and reduces LDLR protein levels (passages labeled Abstract; no page numbers provided). (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Despite the compelling nature of EGFR as a drug target in GBM, the EGFR inhibitors gefitinib and erlotinib have failed to demonstrate efficacy (9–11), in large part as a consequence of persistent PI3K signaling due to PTEN loss and/or coactivation of other receptor tyrosine kinases (9, 10, 12).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Partly supportedcites [9] Mellinghoff, 2005, Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors, N Engl J Med sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) reports that only 10–20% of patients respond to EGFR kinase inhibitors, but it also says a small subgroup benefits from gefitinib or erlotinib. The in vitro studies section (page unavailable) links PTEN loss to resistance, while noting both Akt-dependent and Akt-independent mechanisms. Our copy does not establish coactivation of other receptor tyrosine kinases as a cause of resistance, or show that persistent PI3K signaling largely explains the drugs’ limited efficacy. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [10] Haas-Kogan, 2005, Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib, J Natl Cancer Inst source
- Partly supportedcites [11] Rich, 2004, Phase II trial of gefitinib in recurrent glioblastoma, J Clin Oncol sourceExperimental — accuracy not yet measured
In “Measurement of Therapeutic Effect, Time to Progression, and Survival” (page unavailable), the gefitinib trial reports no complete or partial responses and frequent progression, supporting limited demonstrated efficacy in recurrent GBM. But “Factors Related to Response, Progression, and Survival” (page unavailable) says erlotinib seemed to show activity; it does not establish persistent PI3K signaling, PTEN loss, or coactivation of other receptor tyrosine kinases as the reason for limited efficacy. (LLM, conf=0.85)
- Partly supportedcites [12] Stommel, 2007, Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies, Science sourceExperimental — accuracy not yet measured
On p. 1, the paper reports that PTEN loss can make EGFR inhibitors ineffective by sustaining PI3K activity and proposes that inputs from other RTKs may also limit their efficacy. Its cell-line experiments on p. 2 show that combined RTK inhibition suppresses signaling where single-agent inhibition does not. The paper does not establish that these mechanisms are largely responsible for gefitinib and erlotinib's lack of clinical efficacy in GBM; it presents the broader clinical explanation as a possibility. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Cholesterol metabolism in mammals is controlled through the coordinated action of SREBP and LXR transcription factors (24–26).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Not checked — no full text of the sourcecites [24] Brown, 1997, The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, Cell source
- Partly supportedcites [25] Zelcer, 2006, Liver X receptors as integrators of metabolic and inflammatory signaling, J Clin Invest sourceExperimental — accuracy not yet measured
The section “LXRs are master regulators of whole-body cholesterol homeostasis” supports LXR’s role in cholesterol metabolism. “LXR signaling in intermediary metabolism and energy balance” says LXR upregulates SREBP-1c, but describes that relationship as regulating hepatic lipogenesis, not coordinated control of cholesterol metabolism by both factors. (LLM, conf=0.84)
- Partly supportedcites [26] Hong, 2008, Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors, Curr Opin Genet Dev sourceExperimental — accuracy not yet measured
The Introduction identifies LXRs as central regulators of cholesterol metabolism in mammals. It also links SREBP and LXR transcriptional responses to sterol availability during lymphocyte activation, but does not establish their coordinated control of mammalian cholesterol metabolism generally. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We recently showed that mutant EGFRvIII expressing GBMs promote lipogenesis through PI3K-dependent activation of the master transcriptional regulator SREBP-1, and we demonstrated that this signal was required for tumor survival in vivo (14).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
What the sources say
- Partly supportedcites [14] Guo, 2009, EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy, Sci Signal sourceExperimental — accuracy not yet measured
The Results sections on EGFR–PI3K–Akt signaling and SREBP-1 knockdown show that EGFRvIII promotes SREBP-1 activation and fatty-acid synthesis, and that SREBP-1 knockdown kills EGFRvIII-bearing cells in culture. The in vivo Results show that the lipogenesis inhibitor C75 promotes apoptosis in EGFRvIII-bearing tumors, but do not directly show that PI3K-dependent SREBP-1 activation itself is required for tumor survival in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.84)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Furthermore, the PI3K pathway is hyperactivated not only in GBM, but also in many other cancers including breast, ovarian, endometrial, lung, prostate, renal and lymphocyte (5, 56–58).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Partly supportedcites [5] Wong, 2010, Targeting the PI3K signaling pathway in cancer, Curr Opin Genet Dev sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) describes PI3K-pathway activation across many cancers and identifies pathway-related alterations in breast, prostate and brain cancers; it also discusses endometrial and lung cancers. Our copy does not substantiate the full list: the searched passages do not identify ovarian, renal or lymphocyte cancers as examples of PI3K-pathway hyperactivation. (LLM, conf=0.85)
- Partly supportedcites [56] Wong, Targeting the PI3K signaling pathway in cancer, Curr Opin Genet Dev sourceExperimental — accuracy not yet measured
The Introduction describes widespread PI3K pathway activation in cancer and identifies breast, prostate and brain cancers; the section on concurrent alterations also identifies endometrial cancer, and the paper discusses PI3K-driven lung cancer. The passages do not establish the claim for ovarian, renal or lymphocyte cancers specifically. Page numbers are not available in our copy. (LLM, conf=0.86)
- Partly supportedcites [57] Yuan, 2008, PI3K pathway alterations in cancer: variations on a theme, Oncogene sourceExperimental — accuracy not yet measured
The Introduction and Known mutations in the pathway sections describe widespread PI3K-pathway dysregulation in cancer. The glioblastoma, HER2, and PTEN sections provide examples involving GBM and breast, ovarian, endometrial, lung, and prostate cancers. Our copy does not establish the claim for renal cancer or lymphocyte-derived cancer; its Immune cells section discusses PI3K activation in immune cells within the tumor environment, not cancers of those cells. No page numbers were available in the indexed passages. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [58] Luo, 2003, Targeting the PI3K-Akt pathway in human cancer: rationale and promise, Cancer Cell source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“EGFR amplification, and EGFRvIII activating mutation are the most common oncogenes promoting PI3K signaling in GBM (1, 6).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Supportedcites [1] Furnari, 2007, Malignant astrocytic glioma: genetics, biology, and paths to treatment, Genes Dev source
The EGFR section (page unavailable) reports EGFR amplification in approximately 40% of GBMs and EGFRvIII in 20–30%, calling EGFRvIII the most common EGFR mutant. The Mitogenic signaling pathways section (page unavailable) explains that PI3Ks are recruited to activated receptor tyrosine kinases, and the paper associates PI3K activation profiles with EGFRvIII expression. Together, these passages support the claim’s characterization of these as common EGFR alterations promoting PI3K signaling in GBM. (LLM, conf=0.88)
- Partly supportedcites [6] Cancer Genome Atlas Research Network, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature sourceExperimental — accuracy not yet measured
The Results section on EGFR family activation (page unavailable) reports frequent EGFR activation in primary GBM, focal EGFR amplification, and EGFR alterations in 41 of 91 sequenced cases; it calls vIII the most commonly described EGFR event. The core-pathways Results section places EGFR in the RTK/PI3K pathway, but the paper does not establish that EGFR amplification and EGFRvIII are together the most common oncogenic drivers of PI3K signaling, or give a separate frequency for vIII. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“PI3K signaling is hyperactivated as a consequence of RTK amplifications and activating mutations, PTEN loss, PI3K point mutations and other genetic lesions, providing a core oncogenic pathway in many cancers, including up to 90% of GBMs (6, 8, 55).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Partly supportedcites [6] Cancer Genome Atlas Research Network, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature sourceExperimental — accuracy not yet measured
The Results (Integrative analyses define core pathways required for GBM pathogenesis; page unavailable) report that 86% of sampled GBMs had a genetic event in the combined RTK/PI3K pathway, including RTK aberrations and PTEN lesions. The Discussion also describes RTK/RAS/PI3K deregulation as common in GBM. Those passages support a core pathway and an approximate ‘up to 90%’ figure for pathway alterations, but they do not establish that PI3K signaling itself was hyperactivated in that proportion of GBMs or establish the broader prevalence claim across many cancers. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [8] Chakravarti, 2004, The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas, J Clin Oncol source
- Not checked — no full text of the sourcecites [55] Choe, 2003, Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo, Cancer Res
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Such drugs not only block exogenous LDL uptake, they also actively promote cholesterol removal from cells and intracellular distribution out of the endoplasmic reticulum (ER) (28).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Partly supportedcites [28] Bensinger, 2008, LXR signaling couples sterol metabolism to proliferation in the acquired immune response, Cell sourceExperimental — accuracy not yet measured
The Discussion (page not provided) links LXR-induced ABCG1 expression to sterol efflux and describes redistribution of sterols out of the ER, though it presents the effect of LXR agonists on these processes as a likely mechanism rather than a directly measured outcome. The Results section on cholesterol homeostasis (page not provided) says added LDL did not change proliferation; it does not show that LXR agonists block LDL uptake. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“SREBP-1 expression and/or activity are regulated by PI3K/Akt signaling through mTORC1 in hepatocytes (61), mouse embryonic fibroblasts (62) and in Drosphila (63).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Supportedcites [61] Li, 2010, Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis, Proc Natl Acad Sci U S A source
The Results (Fig. 1B; page not provided) show that insulin-induced SREBP-1c mRNA expression in primary rat hepatocytes was blocked by inhibitors of PI3K, Akt, and mTORC1. Citation (61) is attached to the hepatocyte portion of the sentence, not the claims about mouse embryonic fibroblasts or Drosophila. (LLM, conf=0.93)
- Partly supportedcites [62] Duvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol Cell sourceExperimental — accuracy not yet measured
Citation (62) is attached to the mouse embryonic fibroblast portion of the sentence. In the Results section on SREBP, the paper reports rapamycin-sensitive increases in processed SREBP1 and Srebp1 transcripts in Tsc2-deficient MEFs, supporting regulation through mTORC1. It does not establish the PI3K/Akt step in those MEFs; it cites a separate study for the observation that activated Akt increases processed SREBP1. (LLM, conf=0.83)
- Partly supportedcites [63] Porstmann, 2008, SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth, Cell Metab sourceExperimental — accuracy not yet measured
For the Drosophila portion of the citing sentence, the Results section (“SREBP Is a Target of the PI3K Pathway in Drosophila”) reports that PI3K/Akt signaling activates dSREBP function. But the Discussion says it remains to be investigated whether dSREBP regulation downstream of PI3K requires TOR, so the claimed mTORC1 link in flies is not established by this paper. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Pharmacokinetic and toxicity studies have demonstrated that GW3965 may induce elevated hepatic triglycerides (25).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Partly supportedcites [25] Zelcer, 2006, Liver X receptors as integrators of metabolic and inflammatory signaling, J Clin Invest sourceExperimental — accuracy not yet measured
The section “LXR signaling in intermediary metabolism and energy balance” (page unavailable) reports that synthetic LXR agonists elevate liver triglycerides in mice. It does not identify GW3965 or describe pharmacokinetic and toxicity studies, so it supports the general risk but not the compound-specific attribution. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Further, mTORC1 activation of SREBP-1 has been shown to be essential for regulating lipid and sterol biogenesis (62).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Supportedcites [62] Duvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol Cell source
The Results section reports that mTORC1 increases active SREBP1 and that Srebp1 knockdown reduces mTORC1-dependent lipid biosynthesis in Tsc2−/− cells. It also reports that SREBP1 and SREBP2 are required for mTORC1-induced expression of fatty-acid and sterol biosynthesis genes, while noting that SREBP2 has the more dominant role for sterol genes. (LLM, conf=0.91)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These cell lines have previously been reported (9, 29).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Materials and Methods > Cell lines
What the sources say
- Partly supportedcites [9] Mellinghoff, 2005, Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors, N Engl J Med sourceExperimental — accuracy not yet measured
The U87MG Model section (page unavailable) reports U87MG cells engineered to express EGFR or EGFRvIII, including PTEN-overexpressing cells. Other Cell-Line Models (page unavailable) reports A431 cells. Our copy does not report LN229, T98, H1975, or HeLa, so this source supports only part of the listed cell lines. (LLM, conf=0.88)
- Partly supportedcites [29] Wang, 2006, Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells, Cancer Res sourceExperimental — accuracy not yet measured
The Results and Discussion section identifies U87MG and the U87-EGFR, U87-EGFRvIII, and U87-PTEN-EGFR cell lines, supporting that portion of the identification citation. Our copy does not identify A431, LN229, T98, H1975, or HeLa, so it does not support the full list. Page numbers were not provided in the indexed passages. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Because cellular cholesterol levels depend on the integrated activities of the uptake, efflux and synthesis pathways (44)”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Supportedcites [44] Maxfield, 2010, Cholesterol, the central lipid of mammalian cells, Curr Opin Cell Biol source
The “Transport of cholesterol into and out of cells” section describes cholesterol uptake, cellular synthesis, and export. The “Cellular cholesterol homeostasis” section describes regulation of synthesis in response to cholesterol levels. Together, these passages support the paraphrase; page numbers were not provided in our copy. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with this model, in the absence of extracellular cholesterol, atorvastatin significantly inhibited the growth and promoted cell death of GBM cells (Supplemental Figure 6).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sixty percent growth inhibition was detected in EGFRvIII expressing GBM cells; only half as much was seen in parental U87 cells (Fig. 3A).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > GBM cells depend on extracellular cholesterol levels for growth
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Figure 2E, we detected decreased LDLR expression after lapatinib treatment, in association with decreased p-EGFR, p-Akt and nuclear SREBP-1 staining (Figure 2E).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFR/PI3K/Akt signaling and nuclear SREBP-1 staining correlate with elevated LDLR expression in GBM patient samples
plaincorrelationaln = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, treatment of U87 and U87-EGFRvIII GBM cells for 4 days with the LXR agonist GW3965 resulted in dose-dependent inhibition of growth and promotion of tumor cell death.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > The LXR agonist GW3965 promotes GBM cell death in vitro with enhanced efficacy in EGFRvIII-expressing tumor cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“overexpression of IDOL, which decreases LDLR expression (Figure, 7D), and in combination with atorvastatin treatment, which inhibits endogenous cholesterol synthesis, show remarkable anti-tumor synergy, although neither agent is effective alone (Supplemental Figure 7).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We detected LDLR expression in some tumors that did not stain positive for p-EGFR. However, these samples showed evidence for PI3K pathway activation, as determined by p-Akt staining (p<0.001) (Figure 2C).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFR/PI3K/Akt signaling and nuclear SREBP-1 staining correlate with elevated LDLR expression in GBM patient samples
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In U251 GBM cells, a cell line that expresses relatively little EGFR but expresses abundant levels of c-Met, HGF stimulated Met phosphorylation and promoted SREBP-1 cleavage and LDLR expression (Supplemental Figure. 3E).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFR/PI3K/Akt signaling and nuclear SREBP-1 staining correlate with elevated LDLR expression in GBM patient samples
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Erlotinib treatment inhibited EGFR and Akt phosphorylation, and induced potent suppression of LDLR expression (Figure 1B).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFRvIII upregulates LDLR in GBM in vivo models
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the allosteric mTOR inhibitor rapamycin did not suppress EGF-mediated LDLR expression (Figure 1F), nor did it suppress SREBP-1 cleavage.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFRvIII promotes LDLR expression through a PI3K/Akt-mediated, SREBP-1 dependent pathway
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Erlotinib (10 uM), LY294002 (10 uM) and Akti 1/2 (5 uM) treatment, targeted to block EGFR, PI3K and Akt signaling respectively, each produced potent suppression of EGF-mediated SREBP-1 cleavage and LDLR expression (Figure 1F).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFRvIII promotes LDLR expression through a PI3K/Akt-mediated, SREBP-1 dependent pathway
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GW3965-mediated LDLR degradation in GBM cells took longer, and required a higher drug dose, than did ABCA1 induction (Figure 5, C and D).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > The LXR agonist GW3965 promotes GBM cell death in vitro with enhanced efficacy in EGFRvIII-expressing tumor cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GW3965 treatment strongly induced ABCA1 expression and reduced LDLR expression (Figure 7A).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > LXR agonist inhibits GBM tumor growth in vivo
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GW3965 treatment promoted dose-dependent increases in ABCA1 and IDOL, with a concomitant decrease in LDLR protein level (Figure 5, A–D; Supplemental Figure 5).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > The LXR agonist GW3965 promotes GBM cell death in vitro with enhanced efficacy in EGFRvIII-expressing tumor cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither LDLR knockdown alone, nor IDOL overexpression alone, were sufficient to promote GBM cell death (Figure 6).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > The LXR agonist GW3965 promotes GBM cell death in vitro with enhanced efficacy in EGFRvIII-expressing tumor cells
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Low dose GW3965 (1 or 2 uM) induced ABCA1, but did not diminish LDLR expression or cause GBM cell death (Figure 6, A–C).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > The LXR agonist GW3965 promotes GBM cell death in vitro with enhanced efficacy in EGFRvIII-expressing tumor cells
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Immunoblot analysis of EGFRvIII-expressing GBMs showed abundant LDLR expression, but expression was scarcely detectable in tumors arising from parental U87MG cells (Figure 1A).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFRvIII upregulates LDLR in GBM in vivo models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Increased LDLR mRNA was detectable within 30 minutes of EGF stimulation (Supplementary Figure 1A), resulting in increased LDLR protein expression detectable two hours after stimulation (Figure 1E).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFRvIII promotes LDLR expression through a PI3K/Akt-mediated, SREBP-1 dependent pathway
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that the synthetic LXR agonist GW3965 potently suppresses GBM growth and induces apoptosis in a mouse model (Figure 7)”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The cell line and mouse xenograft models used recapitulate the biology of human GBM sufficiently for conclusions about GBM biology and therapy to hold.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we find that IDOL-mediated degradation of LDLR is necessary, but not sufficient, to induce GBM cell apoptosis (Figure 6).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The cell line and mouse xenograft models used recapitulate the biology of human GBM sufficiently for conclusions about GBM biology and therapy to hold.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“SREBPs promote the expression of genes involved in cholesterol synthesis and enhance the uptake of extracellular cholesterol by inducing expression of the LDL receptor (LDLR).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data demonstrate that an LXR agonist potently inhibits GBM growth and promotes tumor cell death in vivo.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > LXR agonist inhibits GBM tumor growth in vivo
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these results demonstrate that EGFR signaling through Akt is associated with nuclear SREBP-1 and LDLR expression in GBM patients, and other PI3K-activating RTKs can also potentially promote LDLR expression.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > EGFR/PI3K/Akt signaling and nuclear SREBP-1 staining correlate with elevated LDLR expression in GBM patient samples
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Twenty years ago, Rudling and colleagues detected elevated LDL binding and LDLR expression in GBM relative to normal brain (53).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Not checked — no full text of the sourcecites [53] Rudling, 1990, Low density lipoprotein receptor activity in human intracranial tumors and its relation to the cholesterol requirement, Cancer Res
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“mTORC1 appears to be critical for linking PI3K signaling with tumor metabolism (16, 59, 60).”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
What the sources say
- Not checked — no full text of the sourcecites [16] DeBerardinis, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab source
- Not checked — no full text of the sourcecites [59] Engelman, 2006, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism, Nat Rev Genet source
- Not checked — no full text of the sourcecites [60] Yecies, 2011, mTOR links oncogenic signaling to tumor cell metabolism, J Mol Med source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Tumor specimens were obtained according to a protocol approved by the Institutional Review Board of UCLA.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Materials and Methods > Immunohistochemistry and image analysis-based scoring
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, these studies have been conducted largely in non-cancerous cells; the role of mTORC1 in regulating SREBP-1 and cellular metabolism in cancer remains to be elucidated.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although we have previously shown that forced activation of the LXR pathway with highly efficacious synthetic agonists inhibits the growth of rapidly dividing primary cells, the relevance of this effect for transformed cells has not been investigated.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“SCID/Beige mice were bred and kept under defined-flora pathogen-free conditions at the AALAC-approved Animal Facility of the Division of Experimental Radiation Oncology, UCLA.”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Materials and Methods > Xenograft Model
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
The role of cholesterol metabolism in GBM pathogenesis and its association with EGFR/PI3K signaling are unknown.
“The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown.”
The paper relies on this without support.
The potential therapeutic targetability of cholesterol metabolism in GBM is unknown.
“Currently, the role of cholesterol metabolism in EGFR/PI3K-activated tumors, and its potential therapeutic targetability are unknown.”
The paper relies on this without support.
The relevance of the LXR pathway for cancer cell biology remains to be determined.
“However, the potential relevance of this pathway for cancer cell biology remains to be determined.”
The paper relies on this without support.
The molecular mechanisms by which GBM cells obtain sufficient cholesterol and the potential therapeutic targetability of this process are not well understood.
“However, the molecular mechanisms by which GBM cells obtain sufficient cholesterol and the potential therapeutic targetability of this process are not well understood.”
The paper relies on this without support.
The cell line and mouse xenograft models used recapitulate the biology of human GBM sufficiently for conclusions about GBM biology and therapy to hold.
“Isogenic human malignant glioma cells (U87, U87-EGFRvIII) and human primary GBM model GBM39 (31, 32) were implanted into immunodeficient SCID/Beige mice for subcutaneous (s.c.) xenograft studies.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“most cancer cells are characterized by an upregulation of the various pathways responsible for its biosynthesis36,39”
From Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex (2018) · cites this paper as [39]
Experimental — accuracy not yet measured
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Discussion
“overexpression of IDOL, which decreases LDLR expression (Figure, 7D)”
§ An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway > Results > LXR agonist inhibits GBM tumor growth in vivo
“a 25-fold increase in GBM cell apoptosis (Figure 7, D and E).”
Citations
Cites
Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. B., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043330 · Cited by 21,807
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · cited 1×
“PI3K signaling may be central to linking the common genetic perturbations of cancer, such as RTK mutations and PTEN loss, with altered metabolic processes, including the “lipogenic phenotype” common to many cancers, such as GBM (13, 14, 17, 20).”
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
The Cancer Genome Atlas Research Network (2008) · Nature · doi:10.1038/nature07385 · Cited by 7,735
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703
Lipid rafts and signal transduction
Simons, K., & Toomre, D. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35036052 · Cited by 5,371
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,794
Lipid rafts as a membrane-organizing principle
Lingwood, D., & Simons, K. (2010) · Science · doi:10.1126/science.1174621 · Cited by 4,417
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088 · cited 1×
“mTORC1 appears to be critical for linking PI3K signaling with tumor metabolism (16, 59, 60).”
Research works printed but not linked: 1
- Wong, Targeting the PI3K signaling pathway in cancer, Curr Opin Genet Dev, 20, 87, 10.1016/j.gde.2009.11.002 · DOI · Paper page
Cited by
Sorted by citations
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
The multifaceted roles of fatty acid synthesis in cancer
Röhrig, F., & Schulze, A. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.89 · Cited by 1,651
Emerging functions of the EGFR in cancer
Sigismund, S., Avanzato, D., & Lanzetti, L. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12155 · Cited by 1,552
“This represents a point of metabolic vulnerability as these cells depend on cholesterol uptake and are highly sensitive to inhibitors of fatty acid and cholesterol biosynthesis (Guo et al., 2011).”
BackgroundLipid metabolic reprogramming in cancer cells
Beloribi‐Djefaflia, S., Vasseur, S., & Guillaumond, F. (2016) · Oncogenesis · doi:10.1038/oncsis.2015.49 · Cited by 1,418
Santos, C. R., & Schulze, A. (2012) · FEBS Journal · doi:10.1111/j.1742-4658.2012.08644.x · Cited by 1,371
Metadata
- Authors
- Guo, D., Reinitz, F., Youssef, M., Hong, C., Nathanson, D., Akhavan, D., Kuga, D., Amzajerdi, A. N., Soto, H., Zhu, S., Babic, I., Tanaka, K., Dang, J., Iwanami, A., Gini, B., DeJesus, J., Lisiero, D. D., Huang, T. T., Prins, R. M., Wen, P. Y., Robins, H. I., Prados, M. D., DeAngelis, L. M., Mellinghoff, I. K., Mehta, M. P., James, C. D., Chakravarti, A., Cloughesy, T. F., Tontonoz, P., & Mischel, P. S.
- Affiliations
- Northwestern University (US)
- Authors' Affiliations: 1Department of Radiation Oncology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Medical School, Columbus, Ohio; Departments of 2Pathology and Laboratory Medicine, 3Neurosurgery, and 4Neurology, and 5Henry Singleton Brain Tumor Program and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles; 6Howard Hughes Medical Institute, University of California, Los Angeles; 7Department of Neurological Surgery, University of California, San Francisco, California; 8Dana-Farber Cancer Institute, Boston, Massachusetts; 9Department of Medicine, University of Wisconsin–Madison, Madison, Wisconsin; 10Memorial Sloan-Kettering Cancer Center, New York, New York; 11Department of Radiation Oncology, Northwestern University, Chicago, Illinois
- ORCID
- Guo, Deliang
- Reinitz, Felicia
- Hong, Cynthia
- Nathanson, David
- Akhavan, David
- Kuga, Daisuke
- Zhu, Shaojun
- Tanaka, Kazuhiro
- Dang, Julie
- Gini, Beatrice
- Huang, Tiffany T.
- Prins, Robert M.
- Wen, Patrick Y.
- Prados, Michael D.
- DeAngelis, Lisa M.
- Mellinghoff, Ingo K.
- Mehta, Minesh P.
- James, C. David
- Chakravarti, Arnab
- Cloughesy, Timothy F.
- Tontonoz, Peter
- Mischel, Paul S.
- Venue
- Cancer Discovery
- Published
- 2011-10-01
- Volume
- 1
- Issue
- 5
- Pages
- 442-456
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3207317
- OpenAlex
- W2104450983
- Cited by
- 452
- References
- 67
- Citations by year
- 2026: 22 · 2025: 32 · 2024: 31 · 2023: 53 · 2022: 39 · 2021: 52 · 2020: 47 · 2019: 26 · 2018: 23 · 2017: 19 · 2016: 26 · 2015: 22 · 2014: 25 · 2013: 17 · 2012: 14
- FWCI
- 5.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (5u54ca119347-03)
- National Cancer Institute (U54-CA119347, CA 119347)
- National Institute of Neurological Disorders and Stroke (NS072838, R01NS073831, R21 NS072838)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- glioblastoma, liver X receptor agonist, GW3965, EGFRvIII, PI3K/Akt signaling, SREBP1, LDL receptor, LDLR degradation, idols, ABCA1, cholesterol efflux, cholesterol metabolism, lipogenesis, cancer cell death, lapatinib, therapeutic target
- MeSH terms
- Liver X Receptors, Lapatinib, Animals, Brain Neoplasms, Cholesterol, Glioblastoma, HeLa Cells, Humans, Quinazolines, Receptors, LDL, Signal Transduction, Up-Regulation, Mice, SCID, Cell Death, ATP-Binding Cassette Transporters, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Mice, Sterol Regulatory Element Binding Protein 1, Orphan Nuclear Receptors, ATP Binding Cassette Transporter 1, ErbB Receptors
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.
A language model drew the claims from the paper on 2026-10-19, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-19 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (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 ›
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