Abstract
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.
Highlights
Ovarian cancer remains the leading cause of gynecologic cancer-related death in women despite widespread efforts to improve surgical procedures and therapeutic targets [1]
We examined the effect of metformin and phenformin on normal fallopian tube secretory epithelial cells (FTSECs) and high grade serous ovarian cancer (HGSC) proliferation in 2-D growth conditions
Analysis of the effects of biguanides on breast cancer stem cells yielded a different metabolic profile; levels of all ribonucleotide and nucleotide triphosphates (NTPs) were significantly decreased, but no effects were seen on the tricarboxylic acid (TCA) cycle [7]
Summary
Ovarian cancer remains the leading cause of gynecologic cancer-related death in women despite widespread efforts to improve surgical procedures and therapeutic targets [1]. In 2015, 21,290 new ovarian cancer diagnoses were made in the United States, and >66% (14,180) of these women died of the disease [2]. Standard treatment for ovarian cancer involves surgical debulking with the goal of no gross residual disease, followed by combination platinum and taxane chemotherapy. Despite advances there have been only modest improvements in the overall 5- and 10year relative survival rates which remain 46% and 35%, respectively [1]. Repurposing low-toxicity drugs may help improve the progression free and overall survival rates [1]. Understanding the mechanism of how low toxicity drugs affect cancer cells may reveal additional therapeutic targets
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