Abstract
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.
Highlights
Epithelial ovarian cancer (OC) is the leading cause of death from gynecological malignancies and the fifth leading cause of cancer-related death among women in the United States [1]
In support of this hypothesis, we have previously reported that diet-induced obesity (DIO) in the K18-gT121+/-; p53fl/fl; Brca1fl/fl (KpB) OC mouse model results in a tripling of tumor growth [35]
To determine if metformin treatment inhibited complex 1 activity in the OC cell lines, cells were treated with increasing concentrations of metformin for 24 h and the activity of complex 1 was measured by ELISA assay
Summary
Epithelial ovarian cancer (OC) is the leading cause of death from gynecological malignancies and the fifth leading cause of cancer-related death among women in the United States [1]. Hyperinsulinemia, IGF-1 and IGF-1 receptor (IGF-1R) levels are known to be important in OC development and progression [20,21,22,23] through interactions with the downstream PI3K/Akt/mTOR pathway [24,25,26,27] Components of this pathway are often mutated, amplified, or aberrantly expressed in OCs, and are currently being targeted for OC treatment [28,29,30,31,32,33,34]. Given the interplay between obesity, insulin/glucose signaling and OC, we hypothesized that obesity creates a unique environment contributing to the generation of tumors that are metabolically distinct from those developing in a “lean” host milieu. Obesity-driven tumors may have metabolic vulnerabilities that could be targetable for treatment with agents such as metformin
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