Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1α expression in human non-small cell lung cancer cells

Biochim Biophys Acta. 2012 Jun;1822(6):852-61. doi: 10.1016/j.bbadis.2012.02.004. Epub 2012 Feb 12.


Cigarette smoking is not only a documented risk for lung carcinogenesis but also promotes lung cancer development. Nicotine, a major component of cigarette smoke but not a carcinogen by itself, has been found to induce proliferation, invasion and metastasis of non-small cell lung cancer (NSCLC). Here we reported that proinvasive effect of nicotine is analogous to that of hypoxia and involves stabilization and activation of hypoxia-inducible factor (HIF)-1α, a key factor in determining the presence of HIF-1 and expression of its downstream metastasis-associated genes. Furthermore, nicotine-induced upregulation of HIF-1α was dependent on mitochondria-derived reactive oxygen species (ROS). Ecotopic expression of mitochondrial targeted catalase effectively prevented nicotine-induced accumulation of HIF-1α protein. In addition, we demonstrated that the effect of nicotine in upregulation of HIF-1α was mediated by Dihydro-β-erythroidine (DhβE)-sensitive nicotine acetylcholine receptors (nAChRs) and required synergistic cooperation of Akt and mitogen-activated protein kinase (MAPK) pathways. These results suggest that exposure to nicotine could mimic effects of hypoxia to stimulate HIF-1α accumulation and activity that might underlie the high metastatic potential of lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Dihydro-beta-Erythroidine / pharmacology
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mecamylamine / pharmacology
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Nicotine / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species / metabolism*
  • Receptors, Cholinergic / metabolism
  • Smoking / adverse effects
  • Transcription, Genetic


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, Cholinergic
  • Dihydro-beta-Erythroidine
  • Mecamylamine
  • Nicotine
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1