mTOR-Mediated Regulation of Metabolic Pathways in Prostate Cancer

Date

2016-08

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Abstract

Metabolic reprogramming is one of the key features of many cancers including prostate cancer. Interestingly, most prostate cancers demonstrate a marked shift towards increased mitochondrial metabolism following tumorigenesis. To that end, metabolic signatures of the tricarboxylic acid cycle (TCA) cycle, oxidative phosphorylation (OXPHOS) and the hexosamine biosynthetic pathway (HBP) correlate with cancer progression. Recent studies indicate that pharmacological inhibition of key steps in these metabolic pathways block cancer cell growth in vitro and disease progression in vivo. Therefore, understanding the mechanisms that lead to these metabolic alterations could yield new therapeutic targets. Here, we hypothesized that the mTOR-signaling pathway, a master regulator of metabolism and known oncogenic signal in prostate cancer, promoted prostate-cancer growth and progression by regulating pyruvate dehydrogenase, a key enzyme that links glycolysis to the TCA cycle and by inhibiting HBP. We used mass spectrometry-based approaches to quantify the levels of glycolytic, TCA cycle and HBP intermediates upon pharmacological inhibition of mTORC1. We also studied the effects on prostate- cancer cell growth following inhibition of pyruvate dehydrogenase and glutamine-fructose-6-phosphate transaminase 1, which is the rate-limiting enzyme of HBP. We show that upon pharmacological inhibition of mTORC1 the levels of pyruvate are increased in a castration-resistant cell model of prostate cancer (CRPC) while the levels of downstream intermediates of TCA cycle are decreased. On the other hand, the levels of downstream HBP metabolites are increased. This suggests that mTORC1 regulates flux through these metabolic pathways. Additionally, we demonstrate that siRNA-mediated silencing of pyruvate dehydrogenase decreased prostate cancer cell proliferation and survival whereas siRNA-mediated silencing of glutamine-fructose-6-phosphate trans-aminase 1 (GFPT1, increased prostate cancer cell growth. Collectively, our data indicate that mTORC1 increases flux into the TCA cycle via PDH and promotes prostate cancer cell growth and survival. mTORC1 also inhibits the HBP, leading to an oncogenic shift that reroutes glucose potentially toward glycolysis and the pentose phosphate pathway.

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Keywords

Prostate, Pathways

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