Cancer Stem Cells in Small Cell Lung Cancer Cell Line H446: Higher Dependency on Oxidative Phosphorylation and Mitochondrial Substrate-Level Phosphorylation than Non-Stem Cancer Cells

Abstract

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.

uPAR Knockout Results in a Deep Glycolytic and OXPHOS Reprogramming in Melanoma and Colon Carcinoma Cell Lines

“…In our studies, we confirmed the relationship between uPAR and metabolism, which has already been partially observed by Gao C et al [42], using FACS sorted cells for uPAR from a small cell lung cancer cell line. We validated our previous work proving that uPAR overexpression plays a central role in the Warburg-like metabolism of cancer cells.…”

Identifying reproducible cancer-associated highly expressed genes with important functional significances using multiple datasets

“…3a). Besides, the DNA replication pathway19 commonly found by PD and SAM, the other 13 significant pathways are mainly associated with lung cancer, including pentose phosphate pathway20, oxidative phosphorylation921, cysteine and methionine metabolism22, glutathione metabolism101112, biosynthesis of amino acids23, ribosome24, proteasome13, protein processing in endoplasmic reticulum2526, phagosome27 and TNF signaling pathway28. These conservative pathways included many DE genes highly expressed in both cancer and normal tissues, which tended to be missed by SAM.…”

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

“…We recently proposed that most of the ATP synthesized in tumor cells would come from mitochondrial substrate level phosphorylation (mSLP) at the succinate ligase reaction (46). Evidence showing that mSLP can compensate for OxPhos deficiency in cancer is emerging (57)(58)(59)(60). mSLP could also compensate for minimal energy production through glycolysis due to the predominance of the glycolytic pyruvate kinase M2 (PKM2) isoform, which produces less ATP than the PKM1 isoform (61).…”