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Cited by 351Cancer, Lipids, and MetabolismGlioma Diagnosis and TreatmentPI3K/AKT/mTOR signaling in cancer

EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy

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Guo, Deliang, Prins, Robert M., Dang, Julie, Kuga, Daisuke, Iwanami, Akio, Soto, Horacio, Lin, Kelly Y., Huang, Tiffany T. +18 more·2009·Science Signaling
DOI 10.1126/scisignal.2000446PMC PMC2978002
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Abstract

Inhibitors of fatty acid signaling promote apoptosis in glioblastoma cells with highly active EGFR signaling.

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  • 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).”

    From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [14]

    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

  • 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).”

    From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [14]

    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

  • 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).”

    From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [14]

    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

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References 40 · Cited by 351

Research works printed but not linked: 34

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Authors
Guo, D., Prins, R. M., Dang, J., Kuga, D., Iwanami, A., Soto, H., Lin, K. Y., Huang, T. T., Akhavan, D., Hock, M. B., Zhu, S., Kofman, A. A., Bensinger, S. J., Yong, W. H., Vinters, H. V., Horvath, S., Watson, A. D., Kuhn, J. G., Robins, H. I., Mehta, M. P., Wen, P. Y., DeAngelis, L. M., Prados, M. D., Mellinghoff, I. K., Cloughesy, T. F., & Mischel, P. S.
Affiliations
  • University of California, Los Angeles (US)
  • Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
  • The University of Texas at San Antonio Health Science Center (US)
  • University of Wisconsin–Madison (US)
  • Dana-Farber Cancer Institute (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • University of California, San Francisco (US)
Corresponding author
Mischel, Paul S.
ORCID
Venue
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Published
2009-12-15
Volume
2
Issue
101
Pages
ra82-ra82
ISSN
  • 1937-9145 (ISSN-L)
  • 1945-0877
DOI
10.1126/scisignal.2000446
PMC
PMC2978002
OpenAlex
W2099711117
Cited by
351
References
40
Citations by year
2026: 19 · 2025: 18 · 2024: 17 · 2023: 27 · 2022: 27 · 2021: 35 · 2020: 33 · 2019: 19 · 2018: 21 · 2017: 21 · 2016: 23 · 2015: 18 · 2014: 19 · 2013: 16 · 2012: 12
FWCI
4.25
Type
journal article
Language
en
Open access
Locations
  • Science Signaling (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5u54ca119347-03, 5m01rr000079-42)
  • National Cancer Institute (P30CA 54174, P30CA054174, U01CA062399, U01 CA62399, CA 62404, CA-16672, U01CA62422, R01CA108633, U01CA062426, CA 108633, U01CA062412, U54-CA119347, U01CA062407, U01CA062422, CA62412, CA 119347, U01CA062421, U01CA62426, P30CA016672)
  • National Institute of Neurological Disorders and Stroke (R01NS050151, NS 050151)
  • National Center for Research Resources (M01-RR00056, M01RR003186, M01RR000056, M01-RR000079, M01 RR-00079, M01 RR-03186)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
glioblastoma, EGFR signaling, SREBP1, Akt, rapamycin resistance, fatty acid synthesis, EGFRvIII, atorvastatin, HMG-CoA reductase inhibition, cancer metabolism, lapatinib, tumor xenografts
MeSH terms
Lapatinib, Antineoplastic Agents, Brain Neoplasms, Fatty Acids, Glioblastoma, Humans, Hydrolysis, Quinazolines, Signal Transduction, Phosphatidylinositol 3-Kinases, Sirolimus, Protein Transport, Lipogenesis, Proto-Oncogene Proteins c-akt, Sterol Regulatory Element Binding Protein 1, Gene Knockdown Techniques, ErbB Receptors

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