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.
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.
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