Obesity is a significant risk factor for
ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of
metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions.
Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with
metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression. In the
K18-gT121+/-; p53fl/fl; Brca1fl/fl (KpB) mouse model,
metformin inhibited
tumor growth in both lean and obese mice. However, in the obese mice,
metformin decreased
tumor growth by 60%, whereas
tumor growth was only decreased by 32% in the lean mice (p=0.003) compared to vehicle-treated mice. The ovarian
tumors from obese mice had evidence of impaired mitochondrial complex 2 function and energy supplied by omega
fatty acid oxidation rather than glycolysis as compared to lean mice, as assessed by metabolomic profiling. The improved efficacy of
metformin in
obesity corresponded with inhibition of mitochondrial complex 1 and
fatty acid oxidation, and stimulation of glycolysis in only the OCs of obese versus lean mice. In conclusion,
metformin had anti-tumorigenic effects in OC cell lines and the KpB OC pre-clinical mouse model, with increased efficacy in obese versus lean mice. Detected metabolic changes may underlie why ovarian
tumors in obese mice have heightened susceptibility to
metformin.