oligomycins and Carcinoma

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

Ca(2+) plays a fundamental role in the control of a variety of cellular functions, in particular, in energy metabolism and apoptosis. In this study, we show that TGF-beta at concentrations of 0.1-1.0 ng/ml transiently increases the level of intracellular Ca(2+) ([Ca(2+)](in)) in human prostate carcinoma, PC-3U, cells. Experiments with mitochondrial inhibitors (oligomycin and antimycin A) and an inhibitor of endoplasmic reticulum Ca(2+) uptake (BHQ) implied that the effect of TGF-beta1 was due to an effect on the mitochondria. TGF-beta1 treatment resulted in a decrease in ATP synthesis and to a depolarisation, leading to a release of Ca(2+) from mitochondria and decreased activity of the Ca(2+) pumps. Analysis of the mitochondria within the PC-3U cells by polarography and membrane potential-sensitive dye (Rhodamine 123) confirmed that under these experimental conditions, TGF-beta1 inhibited ATP synthesis and depolarised the mitochondria. The results implicate that TGF-beta1 affects the function of the mitochondria and may be of significance for the understanding of the proapoptotic effect of TGF-beta1 in these cells.

Topics: Antimycin A; Calcium; Calcium-Transporting ATPases; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Carcinoma; Cell Line; Endoplasmic Reticulum; Energy Metabolism; Enzyme Inhibitors; Homeostasis; Humans; Male; Membrane Potentials; Mitochondria; Oligomycins; Oxygen; Prostatic Neoplasms; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uncoupling Agents

Topics: Acid Phosphatase; Adenosine Triphosphatases; Adjuvants, Immunologic; Animals; Carcinoma; Endotoxins; Immunosuppressive Agents; Lung Neoplasms; Lymphocytes; Male; Mycobacterium bovis; Neoplasm Proteins; Neoplasms, Experimental; Oligomycins; Propionibacterium acnes; Rats; Sarcoma, Yoshida; Spleen

Topics: Acetaldehyde; Adenosine Diphosphate; Animals; Antimycin A; Atractyloside; Carcinoma; Citrates; Dinitrophenols; Kidney; Kinetics; Liver Neoplasms; Male; Mitochondria; Mitochondria, Liver; Neoplasms, Experimental; Oligomycins; Oxygen Consumption; Rats; Rotenone

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Aerobiosis; Aminoisobutyric Acids; Anaerobiosis; Anti-Bacterial Agents; Biological Transport, Active; Carbon Radioisotopes; Carcinoma; Cell Line; Culture Media; Evaluation Studies as Topic; Glycolysis; Humans; Kinetics; Mouth Neoplasms; Oligomycins; Oxidative Phosphorylation; Potassium; Sodium; Uncoupling Agents

Topics: Adenosine Triphosphatases; Calcium Chloride; Carcinoma; Dinitrophenols; Enzyme Activation; Fluorides; Humans; Lung Diseases; Lung Neoplasms; Lymphocytes; Oligomycins; Ouabain; Potassium; Sodium