Metformin induces distinct bioenergetic and metabolic profiles in sensitive versus resistant high grade serous ovarian cancer and normal fallopian tube secretory epithelial cells
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Melissa Hodeib1,*, Martin P. Ogrodzinski2,3,*, Laurent Vergnes4, Karen Reue4, Beth Y. Karlan1, Sophia Y. Lunt2 and Paul-Joseph P. Aspuria1
1Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
2Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
3Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
4Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Paul-Joseph P. Aspuria, email: [email protected]
Keywords: metformin; ovarian cancer; bioenergetics; metabolomics
Received: July 13, 2017 Accepted: December 08, 2017 Published: December 23, 2017
Metformin is a widely used agent for the treatment of diabetes and infertility, however, it has been found to have anti-cancer effects in a variety of malignancies including high grade serous ovarian cancer (HGSC). Studies describing the mechanisms by which metformin affects HGSC are ongoing, but detailed analysis of its effect on the cellular metabolism of both HGSC cells and their precursor, normal fallopian tube secretory epithelial cells (FTSECs), is lacking. We addressed the effects of metformin and the more potent biguanide, phenformin, on HGSC cell lines and normal immortalized FTSECs. Cell proliferation assays identified that FTSECs and a subset of HGSC cell lines are relatively resistant to the anti-proliferative effects of metformin. Bioenergetic and metabolomic analyses were used to metabolically differentiate the metformin-sensitive and metformin-resistant cell lines. Bioenergetically, biguanides elicited a significant decrease in mitochondrial respiration in all HGSC cells and FTSECs. However, biguanides had a greater effect on mitochondrial respiration in metformin sensitive cells. Metabolomic analysis revealed that metformin and phenformin generally induce similar changes in metabolic profiles. Biguanide treatment led to a significant increase in NADH in FTSECs and HGSC cells. Interestingly, biguanide treatment induced changes in the levels of mitochondrial shuttle metabolites, glycerol-3-phopshate (G3P) and aspartate, specifically in HGSC cell lines and not in FTSECs. Greater alterations in G3P or aspartate levels were also found in metformin sensitive cells relative to metformin resistant cells. These data identify bioenergetic and HGSC-specific metabolic effects that correlate with metformin sensitivity and novel metabolic avenues for possible therapeutic intervention.
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