oligomycins and Lung-Neoplasms

Recently, targeting cancer stem cells (CSCs) metabolism is becoming a promising therapeutic approach to improve cancer treatment outcomes. However, knowledge of the metabolic state of CSCs in small cell lung cancer is still lacking. In this study, we found that CSCs had significantly lower oxygen consumption rate and extracellular acidification rate than non-stem cancer cells. Meanwhile, this subpopulation of cells consumed less glucose, produced less lactate and maintained lower ATP levels. We also revealed that CSCs could produce more ATP through mitochondrial substrate-level phosphorylation during respiratory inhibition compared with non-stem cancer cells. Furthermore, they were more sensitive to suppression of oxidative phosphorylation. Therefore, oligomycin (inhibitor of oxidative phosphorylation) could severely impair sphere-forming and tumor-initiating abilities of CSCs. Our work suggests that CSCs represent metabolically inactive tumor subpopulations which sustain in a state showing low metabolic activity. However, mitochondrial substrate-level phosphorylation of CSCs may be more active than that of non-stem cancer cells. Moreover, CSCs showed preferential use of oxidative phosphorylation over glycolysis to meet their energy demand. These results extend our understanding of CSCs metabolism, potentially providing novel treatment strategies targeting metabolic pathways in small cell lung cancer.

Topics: Adenosine Triphosphate; Animals; Cell Line, Tumor; Cell Proliferation; Energy Metabolism; Extracellular Space; Glucose; Humans; Lactic Acid; Lung Neoplasms; Mice, Nude; Mitochondria; Neoplastic Stem Cells; Oligomycins; Oxidative Phosphorylation; Small Cell Lung Carcinoma; Spheroids, Cellular; Substrate Specificity

The energy metabolism of an atypical multidrug resistant human small cell lung carcinoma cell line (GLC4/ADR) was studied. The glycolytic rate was 30% reduced and the glucose-6-phosphate dehydrogenase activity 2-fold increased in GLC4/ADR compared to the parental sensitive line (GLC4). Although mitochondrial respiration activities were similar in both cell lines, GLC4/ADR was more sensitive to the antimitochondrial drugs doxycycline and oligomycin, while cross-resistance was observed for the glycolytic inhibitor 2-deoxyglucose and for the antimitochondrial drug rhodamine-123. Continuous incubation with doxycycline induced a dramatic reduction of mitochondrial mRNAs in both cell lines, whereas a strong reduction of the nuclear-coded mRNA for subunit IV of cytochrome c oxidase was induced in GLC4/ADR only. Incubation with doxycycline had an additive effect on the cytotoxicity of adriamycin in both cell lines. Thus, a form of collateral sensitivity to antimitochondrial drugs may exist in atypical multidrug resistant cell lines.

Topics: Adenosine Triphosphate; Blotting, Northern; Carcinoma, Small Cell; Cell Line; Cell Survival; Deoxyglucose; Doxorubicin; Doxycycline; Drug Resistance; Electron Transport Complex IV; Energy Metabolism; Fluorescent Dyes; Glucosephosphate Dehydrogenase; Glycolysis; Humans; Kinetics; Lactates; Lung Neoplasms; Mitochondria; NADP; Oligomycins; Oxygen Consumption; Rhodamine 123; Rhodamines; RNA, Neoplasm; Transcription, Genetic

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

Topics: Adenosine Triphosphatases; Adolescent; Adult; Aged; Antigens, Neoplasm; Breast Neoplasms; Dinitrophenols; Female; Gastrointestinal Neoplasms; Humans; Lectins; Lung Neoplasms; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Oligomycins; Ouabain; Stimulation, Chemical