title: Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1α expression in human non-small cell lung cancer cells.
abstract: 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.
authors.affiliation: Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvitoment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Wang
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Pan
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhou
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wu
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008464:Mecamylamine / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D014158:Transcription, Genetic
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011950:Receptors, Cholinergic; D004079:Dihydro-beta-Erythroidine; D008464:Mecamylamine; D009538:Nicotine; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1