oligomycins and Ovarian-Neoplasms

Cellular metabolic changes that accompany malignant transformation have been heralded as hallmark features of cancer. However, metabolic signatures between neoplasms can be unique, allowing for distinctions in malignancy, invasion and chemoresistance between cancer types and subtypes. Mitochondria are central metabolic mediators, as cellular bioenergetics veers from oxidative phosphorylation to glycolysis. Herein, we evaluate the role of mitochondria in maintenance of cellular metabolism, proliferation, and survival in the adult granulosa tumor cell line, KGN, as well as three epithelial ovarian cancer cell lines to determine distinctions in specific features.. Notably, KGN cells were susceptible to TRAIL- and cisplatin-induced death following pretreatment with the metabolic inhibitor FCCP, but not oligomycin A. Collapse of mitochondrial membrane potential was found concomitant with cell death via apoptosis, independent from extrinsic canonical apoptotic routes. Rather, treatment with FCCP resulted in elevated cytochrome c release from mitochondria and decreased responsiveness to BIRC5. Following knockdown of BIRC5, mitochondrial membrane depolarization further sensitized KGN cells to induction of apoptosis via TRAIL.. These results indicate an essential role, distinct from metabolism, for mitochondrial membrane potential in KGN cells to sense and respond to external mediators of apoptotic induction.

Topics: Antineoplastic Agents; Apoptosis; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cell Death; Cell Line, Tumor; Cisplatin; Female; Granulosa Cell Tumor; Humans; Membrane Potential, Mitochondrial; Oligomycins; Ovarian Neoplasms; Proton Ionophores; Survivin; TNF-Related Apoptosis-Inducing Ligand

The way cancer cells escape cisplatin-induced apoptosis has not been completely elucidated yet. We questioned the relevance of "metabolic reprogramming" in cisplatin-resistance by studying mitochondrial function and metabolism in human ovarian carcinoma cell lines, both cisplatin-sensitive (2008) and resistant (C13). C13 cells, in comparison to 2008 cells, showed lower apoptotic response to cisplatin exposure, lower basal oxygen consumption (4.2±0.2 vs 6.5±0.7 fmol/cell/min, p<0.005) and a lower basal transmembrane mitochondrial potential (Δψm) (18.7±1.5 vs 32.2±1 MFI p<0.001). Moreover, C13 cells showed a lower sensitivity to rotenone and oligomycin, two mitochondrial respiratory chain inhibitors. To further investigate the impact of mitochondria on cisplatin-resistance, 2008 and C13 cells were depleted of their mitochondrial DNA (rho(0)-clones). The cytotoxicity of cisplatin was lower in 2008-rho(0)clones than in 2008 cells (IC(50) of 3.56 µM and 0.72 µM, respectively) but similar between C13-rho(0) and C13 cells (IC(50) of 5.49 µM and 6.49 µM, respectively). The time-course of cell viability in glucose-free galactose medium indicated that C13 cells are more strictly dependent on glucose than 2008 cells. (1)H-NMR spectroscopy showed a higher basal content of intracellular glutathione (GSH) and mobile lipids (MLs) in C13 cells as compared to 2008 cells, with higher lipid accumulation mainly within cytoplasmic droplets of the C13 cells. These findings allow us to propose a "metabolic remodelling" of ovarian carcinoma cells to a lipogenic phenotype, which includes alteration of mitochondrial function, as an advantageous mechanism to escape cisplatin-induced apoptosis. This hypothesis is of interest to exploit new pharmacological targets to improve the clinical impact of platinum drugs.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Cell Line, Tumor; Cisplatin; Cytoplasmic Granules; DNA, Mitochondrial; Drug Resistance, Neoplasm; Female; Glucose; Glutathione; Humans; Inhibitory Concentration 50; Lipid Metabolism; Membrane Potential, Mitochondrial; Mitochondria; Oligomycins; Ovarian Neoplasms; Oxidative Phosphorylation; Oxygen Consumption; Rotenone; Uncoupling Agents

Topics: Animals; Azides; Carbon Radioisotopes; Culture Techniques; Cyanides; Depression, Chemical; Dinitrophenols; Female; Mitochondria; Mitochondria, Liver; Oligomycins; Ovarian Neoplasms; Rats; RNA; Rotenone; Time Factors; Uridine

Topics: Animals; Antimetabolites; Antimycin A; Azides; Base Sequence; Carbon Isotopes; Carcinoma, Ehrlich Tumor; Cells, Cultured; Centrifugation, Density Gradient; Cyanides; Dactinomycin; Dinitrophenols; Electrophoresis, Paper; Energy Transfer; Female; Fluorides; Iodoacetates; Kinetics; Mice; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Experimental; Oligomycins; Ovarian Neoplasms; Phosphorus Isotopes; RNA; RNA, Neoplasm; Rotenone