Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 14; pp. 4429 - 4438
• Main Authors: FENDT, Sarah-Maria, BELL, Eric L, PATNAIK, Akash, BLOUIN, Marie Jose, CANTLEY, Lewis C, GUARENTE, Leonard, BLENIS, John, POLLAK, Michael N, OLUMI, Aria F, VANDER HEIDEN, Matthew G, STEPHANOPOULOS, Gregory, KEIBLER, Mark A, DAVIDSON, Shawn M, WIRTH, Gregory J, FISKE, Brian, MAYERS, Jared R, SCHWAB, Matthias, BELLINGER, Gary, CSIBI, Alfredo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-07-2013
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Citric Acid Cycle - drug effects; Disease Models, Animal; Glucose - metabolism; Glutamine - metabolism; Gynecology. Andrology. Obstetrics; Male; Male genital diseases; Medical sciences; Metformin - pharmacology; Mice; Mice, Transgenic; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Oxidation-Reduction; Pharmacology. Drug treatments; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Urinary system disease; Prostate disease; Malignant tumor; Glucose; Metabolism; Biguanides; Aminoacid; Oxidation; Metformin; Pharmacokinetics; Male genital diseases; Prostate cancer; Tumor cell; Cancer; Glutamine
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-0080

Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer 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, whereas 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.