Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance.

Abstract

Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.

• Authors: Kenta Masui, Kazuhiro Tanaka, Shiro Ikegami, Genaro R Villa, Huijun Yang, William H Yong, Timothy F Cloughesy, Kanato Yamagata, Nobutaka Arai, Webster K Cavenee, Paul S Mischel
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 30 Pg. 9406-11 (Jul 28 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26170313 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Carrier Proteins
• Multiprotein Complexes
• RICTOR protein, human
• Rapamycin-Insensitive Companion of mTOR Protein
• Acetyl Coenzyme A
• ErbB Receptors
• AKT1 protein, human
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Glucose

Topics

• Acetates (chemistry)
• Acetyl Coenzyme A (chemistry)
• Acetylation
• Amino Acid Sequence
• Animals
• Brain Neoplasms (drug therapy, metabolism)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• ErbB Receptors (metabolism)
• Gene Expression Regulation, Neoplastic
• Glioblastoma (drug therapy, metabolism)
• Glucose (chemistry)
• Humans
• Mechanistic Target of Rapamycin Complex 2
• Mice
• Mice, SCID
• Molecular Sequence Data
• Multiprotein Complexes (metabolism)
• Neoplasm Transplantation
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-akt (metabolism)
• Rapamycin-Insensitive Companion of mTOR Protein
• Sequence Homology, Amino Acid
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)