Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

TLDR

Metformin has been linked to cancer prevention, yet the mechanisms by which it suppresses tumor growth remain unclear. The study aims to determine whether metformin inhibits mitochondrial complex I activity and cellular respiration in human cancer cells. Metformin blocks complex I, suppresses respiration and proliferation in glucose, induces cell death under glucose deprivation, and these effects are reversed by overexpressing the yeast NADH dehydrogenase NDI1. Metformin reduced HIF‑1 activation, inhibited tumor growth in mice, and these effects were absent in NDI1‑expressing cells, confirming a cell‑autonomous, complex I–dependent mechanism.

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.