title: Nicotine promotes proliferation of human nasopharyngeal carcinoma cells by regulating α7AChR, ERK, HIF-1α and VEGF/PEDF signaling.
abstract: Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis, but the precise mechanisms involved remain largely unknown. Here, we investigated the mechanism of action of nicotine in human nasopharyngeal carcinoma (NPC) cells. Nicotine significantly promoted cell proliferation in a dose and time-dependent manner in human NPC cells. The mechanism studies showed that the observed stimulation of proliferation was accompanied by the nicotine-mediated simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling. Treatment of NPC cells with nicotine markedly upregulated the expression of α7AChR and HIF-1α proteins. Transfection with a α7AChR or HIF-1α-specific siRNA or a α7AChR-selective inhibitor significantly attenuated the nicotine-mediated promotion of NPC cell proliferation. Nicotine also promoted the phosphorylation of ERK1/2 but not JNK and p38 proteins, thereby induced the activation of ERK/MAPK signaling pathway. Pretreatment with an ERK-selective inhibitor effectively reduced the nicotine-induced proliferation of NPC cells. Moreover, nicotine upregulated the expression of VEGF but suppressed the expression of PEDF at mRNA and protein levels, leading to a significant increase of the ratio of VEGF/PEDF in NPC cells. Pretreatment with a α7AChR or ERK-selective inhibitor or transfection with a HIF-1α-specific siRNA in NPC cells significantly inhibited the nicotine-induced HIF-1α expression and VEGF/PEDF ratio. These results therefore indicate that nicotine promotes proliferation of human NPC cells in vitro through simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling and suggest that the related molecules such as HIF-1α might be the potential therapeutic targets for tobacco-associated diseases such as nasopharyngeal carcinomas.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Dingbo
authors.initials: D
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Wangbin
authors.initials: W
authors.lastname: Chen
authors.forename: Lingyi
authors.initials: L
authors.lastname: Fu
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.forename: Yung
authors.initials: Y
authors.lastname: Tian
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D005136:Eye Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009414:Nerve Growth Factors; D009538:Nicotine; D011978:Receptors, Nicotinic; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000099174:Pigment Epithelium-Derived Factor; C579167:Chrna7 protein, human