Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism Nih Public Access Author Manuscript

Correspondence to: Authors Contribution: SMF conceived and designed the study, performed in vitro labeling and proliferation experiments, helped with mouse experiments, measured cell lines and tumor tissue mass distributions and/or metabolite levels, analyzed all data and drafted the manuscript. ELB helped designing the study, helped with mouse experiments, generated TSC2 knockdown cell lines and helped drafting the manuscript. MAK performed HPLC and extracellular metabolite measurements and helped with proliferation experiments. SMD performed mouse labeling experiments. GJW had the initial idea to investigate prostate cancer and metformin. BF and JRM helped with mouse experiments. MS performed metformin measurements. GB helped with mouse experiments. AP provided initial TRAMP mice and helped with mouse experiments. AC, MJB, JB, LCC, LG, and MNP provided advice and support. AFO contributed to the initial idea to investigate prostate cancer and metformin and provided support. MGVH and GS provided conceptual advice and helped drafting the manuscript. Metformin inhibits cancer cell proliferation and epidemiology studies suggest an association with increased survival in cancer patients taking metformin, however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation while increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer.

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