Metabolic actions of metformin in cancer cells and a distinction of metformin from the effects of rotenone, a mitochondrial complex I inhibitor

Abstract

Metformin, the most widely prescribed anti‐diabetes drug, is correlated to a decreased cancer incidence in diabetes patients, and inhibits cancer cell growth in vitro. We examined metabolic actions of metformin in two cell lines: a pluripotent line from an embryonic carcinoma and a metastatic protstate line. Results with both lines were similar. Metformin increased glucose uptake and lactate formation in these cells, while an inhibitor of phosphofructokinase (acting at PFK‐2) inhibited these processes. Metformin stimulated glucose uptake and lactate formation in the presence of the PFK inhibitor. While metformin is known to stimulate fatty acid oxidation in normal cells, it inhibited this process in the cancer cells. This was traced to a metformin induced decrease in cell viability in the cancer cells in the presence of fatty acids. Decreased cell viability was also observed with rotenone, a known mitochondrial complex I inhibitor. We compared the ability of metformin and rotenone to influence the action of rapamycin on cell viability. Unlike metformin, rotenone further decreased the viability of cells in the presence of rapamycin, suggesting the action of rotenone is not limited to inhibition of mTOR. Finally, we found that Compound C, a known inhibitor of AMPK phosphorylation, suppressed the effects of metformin on glucose uptake. We conclude that metformin exerts anti‐cancer effects apart from Complex I, but involving AMPK and mTOR signaling.