Aberrant cellular metabolism has emerged as a hallmark of cancer. In highly proliferating cells including cancer cells, glucose metabolism is diverted from energy (ATP) production to the glycolytic and biosynthetic pathways to enable de novo synthesis of nucleotides, membrane and protein components required for cell proliferation. Signal transduction pathways triggered by growth factor receptors play a role in the metabolic switch. For example, enhanced PI3K/Akt signaling can upregulate glucose uptake and flux through glycolysis. Reciprocally, metabolic intermediates and enzymes could impinge on signaling molecules as well. How this bidirectional regulation can be orchestrated to promote cellular proliferation is poorly understood. Identifying critical signaling molecules that couple metabolism with cell proliferation would provide insights for development of new therapeutic targets not only for cancer but other diseases that are impacted by high cellular proliferation rates and defective metabolism such as diabetes and autoimmune disorders. Our proposed studies will examine how mTORC2 can serve as a switch that links the metabolic biosynthetic pathway to cellular proliferation. Our studies will uncover novel insights on the significance of the Warburg effect (enhanced aerobic glycolysis) on tumorigenesis and how a key signaling molecule (mTOR) can control the metabolic biosynthetic pathway to promote proliferation. Our findings will have direct implications for the development of novel therapeutic targets for diseases impacted by high proliferation and altered metabolism such as cancer, diabetes, and autoimmune disorders.

Public Health Relevance

The control of cell proliferation is linked to cellular metabolism but the mechanisms that couple these processes are poorly understood. Our proposal will address how the mammalian target of rapamycin (mTOR) as part of mTORC2 couples metabolism to proliferation via its function in cotranslational maturation of key enzymes involved in the glycolytic/biosynthetic pathways. We will particularly focus on the hexosamine biosynthetic pathway, which produces metabolites necessary for glycosylation of membrane and intracellular proteins. Our studies will reveal insights how combined inhibition of mTORC2 and its targeted biosynthetic enzymes can be effective for treatment of diseases with abnormal metabolism and proliferation such as cancer, diabetes and autoimmune disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079176-09
Application #
9135436
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Maas, Stefan
Project Start
2008-04-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Rbhs-Robert Wood Johnson Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
Moloughney, Joseph G; Vega-Cotto, Nicole M; Liu, Sharon et al. (2018) mTORC2 modulates the amplitude and duration of GFAT1 Ser-243 phosphorylation to maintain flux through the hexosamine pathway during starvation. J Biol Chem 293:16464-16478
Weiss, Harvey R; Chi, Oak Z; Kiss, Geza K et al. (2018) Akt activation improves microregional oxygen supply/consumption balance after cerebral ischemia-reperfusion. Brain Res 1683:48-54
Moloughney, Joseph G; Kim, Peter K; Vega-Cotto, Nicole M et al. (2016) mTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1. Mol Cell 63:811-26
Chi, Oak Z; Wu, Chang-Chih; Liu, Xia et al. (2015) Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis. Neuromolecular Med 17:305-13
Chou, Po-Chien; Oh, Won Jun; Wu, Chang-Chih et al. (2014) Mammalian target of rapamycin complex 2 modulates ??TCR processing and surface expression during thymocyte development. J Immunol 193:1162-70
Destefano, Michael A; Jacinto, Estela (2013) Regulation of insulin receptor substrate-1 by mTORC2 (mammalian target of rapamycin complex 2). Biochem Soc Trans 41:896-901
Kim, Sung Jin; DeStefano, Michael A; Oh, Won Jun et al. (2012) mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. Mol Cell 48:875-87
Su, Bing; Jacinto, Estela (2011) Mammalian TOR signaling to the AGC kinases. Crit Rev Biochem Mol Biol 46:527-47
Jacinto, Estela (2011) TFEBulous control of traffic by mTOR. EMBO J 30:3215-6
Oh, Won Jun; Jacinto, Estela (2011) mTOR complex 2 signaling and functions. Cell Cycle 10:2305-16

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