Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis.
Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.DOI: http://dx.doi.org/10.7554/eLife.02242.001.
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
William W
WW
Wheaton
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Samuel E
SE
Weinberg
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Robert B
RB
Hamanaka
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Saul
S
Soberanes
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Lucas B
LB
Sullivan
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Elena
E
Anso
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Andrea
A
Glasauer
Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
Eric
E
Dufour
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Gokhan M
GM
Mutlu
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Gr Scott
GS
Budigner
Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States nav@northwestern.edu.
Navdeep S
NS
Chandel
D063646:Carcinogenesis; D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000187:drug effects*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology
D008687:Metformin; D042967:Electron Transport Complex I
cancer; metformin; mitochondria