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 dehydrog...
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doaj-ab1cc35411e44f338acc368baee076d92021-05-04T23:08:28ZengeLife Sciences Publications LtdeLife2050-084X2014-05-01310.7554/eLife.02242Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesisWilliam W Wheaton0Samuel E Weinberg1Robert B Hamanaka2Saul Soberanes3Lucas B Sullivan4Elena Anso5Andrea Glasauer6Eric Dufour7Gokhan M Mutlu8GR Scott Budigner9Navdeep S Chandel10Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesInstitute of Biomedical Technology, University of Tampere, Tampere, FinlandDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesDepartment of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, United StatesRecent 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.https://elifesciences.org/articles/02242metformincancermitochondria |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
William W Wheaton Samuel E Weinberg Robert B Hamanaka Saul Soberanes Lucas B Sullivan Elena Anso Andrea Glasauer Eric Dufour Gokhan M Mutlu GR Scott Budigner Navdeep S Chandel |
spellingShingle |
William W Wheaton Samuel E Weinberg Robert B Hamanaka Saul Soberanes Lucas B Sullivan Elena Anso Andrea Glasauer Eric Dufour Gokhan M Mutlu GR Scott Budigner Navdeep S Chandel Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis eLife metformin cancer mitochondria |
author_facet |
William W Wheaton Samuel E Weinberg Robert B Hamanaka Saul Soberanes Lucas B Sullivan Elena Anso Andrea Glasauer Eric Dufour Gokhan M Mutlu GR Scott Budigner Navdeep S Chandel |
author_sort |
William W Wheaton |
title |
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis |
title_short |
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis |
title_full |
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis |
title_fullStr |
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis |
title_full_unstemmed |
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis |
title_sort |
metformin inhibits mitochondrial complex i of cancer cells to reduce tumorigenesis |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2014-05-01 |
description |
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. |
topic |
metformin cancer mitochondria |
url |
https://elifesciences.org/articles/02242 |
work_keys_str_mv |
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