mTOR Complex 2 Controls Glycolytic Metabolism in Glioblastoma through FoxO Acetylation and Upregulation of c-Myc
Open accessAbstract
Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
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mTOR is a conserved serine/threonine kinase that plays a key role in integrating multiple physiological stimuli to regulate cell growth and metabolic pathways.
“mTOR is a conserved serine/threonine kinase that plays a key role in integrating multiple physiological stimuli to regulate cell growth and metabolic pathways27,28,40,48.”
From RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression (2020) · cites this paper as [40]
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“mTORC2 responds to activation of Akt, SGK, and PKC, and controls cell survival, size, and glycolytic metabolism through FoxO transcription factors (Jacinto et al. 2004; Inoki and Guan 2006; Masui et al. 2013).”
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- Authors
- Masui, K., Tanaka, K., Akhavan, D., Babic, I., Gini, B., Matsutani, T., Iwanami, A., Liu, F., Villa, G. R., Gu, Y., Campos, C., Zhu, S., Yang, H., Yong, W. H., Cloughesy, T. F., Mellinghoff, I. K., Cavenee, W. K., Shaw, R. J., & Mischel, P. S.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- Memorial Sloan Kettering Cancer Center (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Mischel, Paul S.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 18
- Issue
- 5
- Pages
- 726-739
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3840163
- OpenAlex
- W2160757449
- Cited by
- 407
- References
- 47
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 26 · 2023: 40 · 2022: 30 · 2021: 31 · 2020: 45 · 2019: 35 · 2018: 31 · 2017: 35 · 2016: 39 · 2015: 29 · 2014: 28 · 2013: 1
- FWCI
- 11.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Foundation for Cancer Research
- Ben and Catherine Ivy Foundation
- National Institutes of Health (NS73831, CA151819, P01-CA95616)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- mTORC2, glioblastoma, aerobic glycolysis, Warburg effect, c-Myc, histone deacetylase, miR-34c, tumor metabolic reprogramming, Akt-independent signaling, patient survival
- MeSH terms
- Forkhead Box Protein O1, Forkhead Box Protein O3, Mechanistic Target of Rapamycin Complex 2, Phosphoinositide-3 Kinase Inhibitors, Acetylation, Animals, Brain Neoplasms, Glioblastoma, Glucose, Glycolysis, Histone Deacetylases, Humans, Models, Biological, Signal Transduction, Up-Regulation, Proto-Oncogene Proteins c-myc, Cell Death, Phosphatidylinositol 3-Kinases, MicroRNAs, Multiprotein Complexes, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Mice, Forkhead Transcription Factors, TOR Serine-Threonine Kinases
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