Cisplatin exposure causes metabolic stress and adaptation in ovarian cancer cells.
Rattan R, Buekers TE, Chhina J, Uddin MH, Giri S, and Munkarah AR. Cisplatin exposure causes metabolic stress and adaptation in ovarian cancer cells. Gynecol Oncol 2017; 145:110.
Objective: Ovarian cancer (OvCa) cells that are highly aggressive or possess cancer-stem-like properties exhibit a “high metabolically active” phenotype, reflected by an increased use of glycolysis and oxidative phosphorylation (OXPHOS) for energy requirements. The aim of our study was to determine whether acquired resistance to cisplatin is associated with an energy metabolic flip towards a high metabolically active phenotype. Method: Extracellular Flux bioanalyzer was used to determine the bioenergetic phenotype of chemosensitive (A2780 and PEO1), their chemoresistant isogeneic (C200 and PEO4) OvCa cell lines, and 15 individual patient-derived OvCa specimens. Real-time measurements of glycolysis and OXPHOS were made. Results: Chemosensitive and-resistant OvCa cell lines showed distinct bioenergetic phenotypes. Resistant cells displayed high glycolysis and OXPHOS defined as high metabolically active phenotype, while the sensitive cells displayed a glycolytic phenotype. Cisplatin exposure to A2780 cells caused an increase in OXPHOS (P b 0.001) and glycolysis (P b 0.01), thus shifting the phenotype toward high metabolically active. Expression of energy metabolism genes in sensitive cells showed an increase in mitochondrial biogenesis genes (P b 0.05) after cisplatin treatment. Combination treatment of cisplatin and inhibitor of mitochondrial ATP synthase in resistant cells resulted in higher cytotoxicity compared to combination of glycolysis inhibition and cisplatin or cisplatin alone (P b 0.01). In OvCa cells obtained from patient specimens, response to cisplatin treatment correlated with their metabolic phenotype. Patient OvCa cells with high metabolically active phenotype were relatively resistant to platinum treatment compared to glycolytic cells. Conclusion: Response to cisplatin correlated with the energy metabolic phenotype of the OvCa cells. Resistant cells are likely to be high metabolically active for adaptation, while sensitive cells are glycolytic. The metabolic phenotype of the ovarian cancer cells from patients may be an indicator of their platinum sensitivity. Combining metabolic inhibitors with cisplatin may offer a new therapeutic approach to reverse resistance to platinum.