title: Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism.
abstract: 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.
authors.affiliation: Departments of Chemical Engineering and Biology, Massachusetts Institute of Technology, Cambridge, MA02139, USA.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Keibler
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Wirth
authors.forename: Brian
authors.initials: B
authors.lastname: Fiske
authors.forename: Jared R
authors.initials: JR
authors.lastname: Mayers
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Gary
authors.initials: G
authors.lastname: Bellinger
authors.forename: Alfredo
authors.initials: A
authors.lastname: Csibi
authors.forename: Akash
authors.initials: A
authors.lastname: Patnaik
authors.forename: Marie Jose
authors.initials: MJ
authors.lastname: Blouin
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.forename: Aria F
authors.initials: AF
authors.lastname: Olumi
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D005973:Glutamine; D008687:Metformin; D005947:Glucose