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Cited by 452Cancer, Lipids, and MetabolismGlioma Diagnosis and TreatmentCholesterol and Lipid Metabolism

An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway

Open access
Guo, Deliang, Reinitz, Felicia, Youssef, Mary, Hong, Cynthia, Nathanson, David, Akhavan, David, Kuga, Daisuke, Amzajerdi, Ali Nael +22 more·2011·Cancer Discovery
DOI 10.1158/2159-8290.cd-11-0102PMC PMC3207317

Published version of a preprint

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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

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1158/2159-8290.cd-11-0102

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

35 of 50 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    PI3K signaling may be central to linking 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.

    “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).”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [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
    • cites [14] Guo, 2009, EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy, Sci Signal source

      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)

      Experimental — accuracy not yet measured
    • cites [17] Heiden, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science source

      “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)

      Experimental — accuracy not yet measured
    • cites [20] Shaw, 2006, Ras, PI(3)K and mTOR signalling controls tumour cell growth, Nature source
  • Premisecitation

    Other RTKs that can be co-expressed in GBM, including c-MET, PDGFR-alpha and PDGFR-beta, can also engage PI3K signaling, resulting in EGFR inhibitor resistance.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Stommel, 2007, Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies, Science source

      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)

      Experimental — accuracy not yet measured
  • Interpretationown data

    Other PI3K pathway activating lesions commonly found in GBM, such as activation of other RTKs, could also promote increased LDLR expression.

    “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.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [6] Cancer Genome Atlas Research Network, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature source
    • cites [12] Stommel, 2007, Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies, Science source
    • cites [39] Wheeler, 2010, Understanding resistance to EGFR inhibitors—impact on future treatment strategies, Nat Rev Clin Oncol source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    Limiting intracellular sterol availability by pharmacologically driving the LXR pathway inhibits the proliferation of rapidly dividing cell types such as lymphocytes.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] Bensinger, 2008, LXR signaling couples sterol metabolism to proliferation in the acquired immune response, Cell source

      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)

      Experimental — accuracy not yet measured
  • Findingown data

    SREBP-1 activation and consequent LDLR expression are rapamycin resistant in preclinical models and in GBM patients treated with rapamycin.

    “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).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] Guo, 2009, EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy, Sci Signal source

      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)

      Experimental — accuracy not yet measured
    • cites [64] Cloughesy, 2008, Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma, PLoS Med source

      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)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 19
  • May combine two claims. 28

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cancer cells preferentially metabolize glucose by aerobic glycolysis, the Warburg effect.

    “Cancer cells preferentially metabolize glucose by aerobic glycolysis, a phenomenon known as the Warburg effect.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [16] DeBerardinis, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab source
    • cites [17] Heiden, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science source
    • cites [18] Kroemer, 2008, Tumor cell metabolism: cancer's Achilles' heel, Cancer Cell source
    • cites [19] Menendez, 2007, Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis, Nat Rev Cancer source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [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 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)

      Experimental — accuracy not yet measured
    • cites [7] Parsons, 2008, An integrated genomic analysis of human glioblastoma multiforme, Science source

      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)

      Experimental — accuracy not yet measured
    • cites [8] Chakravarti, 2004, The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas, J Clin Oncol source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science source

  • May combine two claims.

    Premisecitation

    The EGFR inhibitors gefitinib and erlotinib have failed to demonstrate efficacy in GBM, largely as a consequence of persistent PI3K signaling due to PTEN loss and/or coactivation of other receptor tyrosine kinases.

    “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).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [9] Mellinghoff, 2005, Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors, N Engl J Med source

      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)

      Experimental — accuracy not yet measured
    • cites [10] Haas-Kogan, 2005, Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib, J Natl Cancer Inst source
    • cites [11] Rich, 2004, Phase II trial of gefitinib in recurrent glioblastoma, J Clin Oncol source

      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)

      Experimental — accuracy not yet measured
    • cites [12] Stommel, 2007, Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies, Science source

      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)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Cholesterol metabolism in mammals is controlled through the coordinated action of SREBP and LXR transcription factors.

    “Cholesterol metabolism in mammals is controlled through the coordinated action of SREBP and LXR transcription factors (24–26).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [24] Brown, 1997, The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, Cell source
    • cites [25] Zelcer, 2006, Liver X receptors as integrators of metabolic and inflammatory signaling, J Clin Invest source

      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)

      Experimental — accuracy not yet measured
    • cites [26] Hong, 2008, Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors, Curr Opin Genet Dev source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mutant EGFRvIII expressing GBMs promote lipogenesis through PI3K-dependent activation of SREBP-1, and this signal is required for tumor survival in vivo.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Guo, 2009, EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy, Sci Signal source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The PI3K pathway is hyperactivated not only in GBM, but also in many other cancers including breast, ovarian, endometrial, lung, prostate, renal and lymphocyte.

    “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).”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [5] Wong, 2010, Targeting the PI3K signaling pathway in cancer, Curr Opin Genet Dev source

      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)

      Experimental — accuracy not yet measured
    • cites [56] Wong, Targeting the PI3K signaling pathway in cancer, Curr Opin Genet Dev source

      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)

      Experimental — accuracy not yet measured
    • cites [57] Yuan, 2008, PI3K pathway alterations in cancer: variations on a theme, Oncogene source

      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)

      Experimental — accuracy not yet measured
    • cites [58] Luo, 2003, Targeting the PI3K-Akt pathway in human cancer: rationale and promise, Cancer Cell source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EGFR amplification and EGFRvIII activating mutation are the most common oncogenes promoting PI3K signaling in GBM.

    “EGFR amplification, and EGFRvIII activating mutation are the most common oncogenes promoting PI3K signaling in GBM (1, 6).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [1] Furnari, 2007, Malignant astrocytic glioma: genetics, biology, and paths to treatment, Genes Dev source
    • cites [6] Cancer Genome Atlas Research Network, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [6] Cancer Genome Atlas Research Network, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature source

      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)

      Experimental — accuracy not yet measured
    • cites [8] Chakravarti, 2004, The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas, J Clin Oncol source
    • cites [55] Choe, 2003, Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo, Cancer Res

  • May combine two claims.

    Premisecitation

    LXR agonists not only block exogenous LDL uptake, they also actively promote cholesterol removal from cells and intracellular distribution out of the endoplasmic reticulum.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] Bensinger, 2008, LXR signaling couples sterol metabolism to proliferation in the acquired immune response, Cell source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SREBP-1 expression and/or activity are regulated by PI3K/Akt signaling through mTORC1 in hepatocytes, mouse embryonic fibroblasts and Drosophila.

    “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).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [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
    • cites [62] Duvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol Cell source

      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)

      Experimental — accuracy not yet measured
    • cites [63] Porstmann, 2008, SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth, Cell Metab source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pharmacokinetic and toxicity studies have demonstrated that GW3965 may induce elevated hepatic triglycerides.

    “Pharmacokinetic and toxicity studies have demonstrated that GW3965 may induce elevated hepatic triglycerides (25).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Zelcer, 2006, Liver X receptors as integrators of metabolic and inflammatory signaling, J Clin Invest source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mTORC1 activation of SREBP-1 is essential for regulating lipid and sterol biogenesis.

    “Further, mTORC1 activation of SREBP-1 has been shown to be essential for regulating lipid and sterol biogenesis (62).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Duvel, 2010, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol Cell source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The U87, U87-EGFRvIII, U87-EGFR, U87-EGFR-PTEN, A431, LN229, T98, H1975 and HeLa cell lines have previously been reported.

    “These cell lines have previously been reported (9, 29).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [9] Mellinghoff, 2005, Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors, N Engl J Med source

      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)

      Experimental — accuracy not yet measured
    • cites [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 source

      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)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Cellular cholesterol levels depend on the integrated activities of the uptake, efflux and synthesis pathways.

    “Because cellular cholesterol levels depend on the integrated activities of the uptake, efflux and synthesis pathways (44)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [44] Maxfield, 2010, Cholesterol, the central lipid of mammalian cells, Curr Opin Cell Biol source

  • May combine two claims.

    Findingown data

    In the absence of extracellular cholesterol, atorvastatin significantly inhibits growth and promotes cell death of GBM cells.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In U87MG and U87MG-EGFRvIII GBM cells cultured in lipoprotein deficient serum (LPDS), 60% growth inhibition is detected in EGFRvIII expressing GBM cells, and only half as much is seen in parental U87 cells.

    “Sixty percent growth inhibition was detected in EGFRvIII expressing GBM cells; only half as much was seen in parental U87 cells (Fig. 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In two GBM patients treated with lapatinib, decreased LDLR expression is detected after treatment, in association with decreased p-EGFR, p-Akt, and nuclear SREBP-1 staining.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of U87 and U87-EGFRvIII GBM cells with the LXR agonist GW3965 for 4 days results in dose-dependent inhibition of growth and promotion of tumor cell death.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpression of IDOL in combination with atorvastatin treatment shows anti-tumor synergy, whereas neither agent alone is effective.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LDLR expression is detected in some tumors that do not stain positive for p-EGFR; these samples show evidence for PI3K pathway activation as determined by p-Akt staining (p<0.001).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In U251 GBM cells, HGF stimulates Met phosphorylation and promotes SREBP-1 cleavage and LDLR expression.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mice bearing EGFRvIII-expressing tumors, erlotinib treatment (150 mg/kg for 7 days) inhibits EGFR and Akt phosphorylation and suppresses LDLR expression.

    “Erlotinib treatment inhibited EGFR and Akt phosphorylation, and induced potent suppression of LDLR expression (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The allosteric mTOR inhibitor rapamycin does not suppress EGF-mediated LDLR expression or SREBP-1 cleavage.

    “In contrast, the allosteric mTOR inhibitor rapamycin did not suppress EGF-mediated LDLR expression (Figure 1F), nor did it suppress SREBP-1 cleavage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Erlotinib, LY294002, and Akti 1/2 each produce potent suppression of EGF-mediated SREBP-1 cleavage and LDLR expression in GBM cells.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GW3965-mediated LDLR degradation in GBM cells takes longer and requires a higher drug dose than ABCA1 induction.

    “GW3965-mediated LDLR degradation in GBM cells took longer, and required a higher drug dose, than did ABCA1 induction (Figure 5, C and D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In mice implanted subcutaneously with U87/EGFRvIII cells and treated with GW3965 (40 mg/kg daily by oral gavage) for 12 days, GW3965 strongly induces ABCA1 expression and reduces LDLR expression.

    “GW3965 treatment strongly induced ABCA1 expression and reduced LDLR expression (Figure 7A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GW3965 treatment promotes dose-dependent increases in ABCA1 and IDOL, with a concomitant decrease in LDLR protein level.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither LDLR knockdown alone nor IDOL overexpression alone is sufficient to promote GBM cell death.

    “Neither LDLR knockdown alone, nor IDOL overexpression alone, were sufficient to promote GBM cell death (Figure 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Low dose GW3965 (1 or 2 uM) induces ABCA1 but does not diminish LDLR expression or cause GBM cell death.

    “Low dose GW3965 (1 or 2 uM) induced ABCA1, but did not diminish LDLR expression or cause GBM cell death (Figure 6, A–C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In U87MG xenografts, EGFRvIII-expressing tumors show abundant LDLR expression, whereas parental U87MG tumors show scarcely detectable LDLR expression.

    “Immunoblot analysis of EGFRvIII-expressing GBMs showed abundant LDLR expression, but expression was scarcely detectable in tumors arising from parental U87MG cells (Figure 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    EGF stimulation of U87MG cells stably over-expressing wild-type EGFR increases LDLR mRNA within 30 minutes and LDLR protein within 2 hours.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The synthetic LXR agonist GW3965 potently suppresses GBM growth and induces apoptosis in a mouse model.

    “Here we show that the synthetic LXR agonist GW3965 potently suppresses GBM growth and induces apoptosis in a mouse model (Figure 7)”
    Quote in the paperSubstantial claim
    • 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.

  • May combine two claims.

    Findingown data

    IDOL-mediated degradation of LDLR is necessary, but not sufficient, to induce GBM cell apoptosis.

    “we find that IDOL-mediated degradation of LDLR is necessary, but not sufficient, to induce GBM cell apoptosis (Figure 6).”
    Quote in the paperSubstantial claim
    • 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.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    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).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    An LXR agonist potently inhibits GBM growth and promotes tumor cell death in vivo.

    “These data demonstrate that an LXR agonist potently inhibits GBM growth and promotes tumor cell death in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rudling and colleagues detected elevated LDL binding and LDLR expression in GBM relative to normal brain.

    “Twenty years ago, Rudling and colleagues detected elevated LDL binding and LDLR expression in GBM relative to normal brain (53).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Rudling, 1990, Low density lipoprotein receptor activity in human intracranial tumors and its relation to the cholesterol requirement, Cancer Res

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mTORC1 appears to be critical for linking PI3K signaling with tumor metabolism.

    “mTORC1 appears to be critical for linking PI3K signaling with tumor metabolism (16, 59, 60).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] DeBerardinis, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab source
    • cites [59] Engelman, 2006, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism, Nat Rev Genet source
    • cites [60] Yecies, 2011, mTOR links oncogenic signaling to tumor cell metabolism, J Mol Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Tumor specimens were obtained according to a protocol approved by the Institutional Review Board of UCLA.

    “Tumor specimens were obtained according to a protocol approved by the Institutional Review Board of UCLA.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The role of mTORC1 in regulating SREBP-1 and cellular metabolism in cancer remains to be elucidated.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Forced activation of the LXR pathway with highly efficacious synthetic agonists inhibits the growth of rapidly dividing primary cells.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim
43 of 43

  • 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.”
5 of 5

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.

  • Figure 7D is cited for two different experiments

    Minor

    The discussion cites Figure 7D for IDOL overexpression decreasing LDLR expression, but the results identify Figures 7D and 7E as showing the increase in apoptosis after GW3965 treatment in vivo. The IDOL overexpression experiment is instead assigned to Figure 6E and 6F in the results.

1 of 1

Cites

Flagged first, then by citations

2 of the 67 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  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

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Related

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
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2011-10-01
Volume
1
Issue
5
Pages
442-456
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-11-0102
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
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 › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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