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Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis
William W Wheaton1, Samuel E Weinberg1, Robert B Hamanaka1
1Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United States.
Abstract:
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.
Insights
The anti-diabetic drug metformin prevents cancer progression by inhibiting mitochondrial complex I activity. This mechanism shows that metformin
Area of Science:
- Biochemistry
- Cancer Biology
- Metabolism
Background:
- Epidemiological and laboratory studies suggest metformin, an anti-diabetic drug, possesses anti-cancer properties.
- The precise mechanisms by which metformin inhibits tumor growth remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying metformin's anti-cancer effects.
- To investigate the role of mitochondrial complex I inhibition in metformin's anti-proliferative activity.
Main Methods:
- Inhibition of mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration in human cancer cells.
- Assessment of cellular proliferation and survival under varying glucose conditions.
- Evaluation of hypoxic activation of hypoxia-inducible factor 1 (HIF-1).
- Overexpression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) to assess resistance to metformin effects.
- In vivo studies using mouse models with metformin administration.
Main Results:
- Metformin inhibits mitochondrial complex I activity and cellular respiration in human cancer cells.
- Metformin suppresses proliferation in the presence of glucose but induces cell death upon glucose deprivation, highlighting cancer cell reliance on glycolysis.
- Metformin reduces hypoxic activation of HIF-1.
- Overexpression of NDI1 reversed metformin's inhibitory effects on proliferation and cell death.
- In vivo, metformin inhibited tumor growth in control cells but not in NDI1-expressing cells.
Conclusions:
- Metformin's anti-cancer effects are cell-autonomous and directly linked to its inhibition of mitochondrial complex I.
- Cancer cells' dependence on glycolysis for survival in the presence of metformin is a critical factor.
- Targeting mitochondrial complex I represents a potential therapeutic strategy in cancer treatment.