Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo

Simple Summary Although the anticancer effects of metformin are well studied, its effect on energy metabolism of cancer cells remains elusive. Metformin can alter the metabolism of cells either by activating AMPK or inhibiting the mitochondrial respiratory chain complex. The aim of the study was to explore the distinct metabolic profiles of ovarian cancer cell lines post-metformin treatment and to understand metformin's metabolism-based anti-growth effect on ovarian cancer cell lines. In this study, using the untargeted metabolomics approach, we found that metformin treatment promoted omega-3 fatty acid metabolism in three different ovarian cancer cell lines, and treating ovarian xenografts with specific omega-3 fatty acids, especially EPA, reduced ovarian tumor growth. Thus, our study adds an additional potential therapeutic mechanism to the multi-potent anticancer effects of metformin. Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin's antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers.