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

PLoS One. 2016 May 11;11(5):e0154576. doi: 10.1371/journal.pone.0154576. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Energy Metabolism / drug effects
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Glucose / metabolism
  • Humans
  • Lactic Acid / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice, Nude
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Oligomycins / pharmacology
  • Oxidative Phosphorylation* / drug effects
  • Small Cell Lung Carcinoma / metabolism*
  • Small Cell Lung Carcinoma / pathology*
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Substrate Specificity / drug effects

Substances

  • Oligomycins
  • Lactic Acid
  • Adenosine Triphosphate
  • Glucose

Grants and funding

This study was supported by the Research Program of the Applied Basic and Cutting-edge Technologies of Tianjin under Contract No. 14JCZDJC35500.