Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells

Abstract

Tobacco-related diseases such as lung cancer cause over 4.2 million deaths annually, with approximately 400,000 deaths per year occurring in the US. Genotoxic effects of tobacco components have been described, but effects on signaling pathways in normal cells have not been described. Here, we show activation of the serine/threonine kinase Akt in nonimmortalized human airway epithelial cells in vitro by two components of cigarette smoke, nicotine and the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Activation of Akt by nicotine or NNK occurred within minutes at concentrations achievable by smokers and depended upon α3-/α4-containing or α7-containing nicotinic acetylcholine receptors, respectively. Activated Akt increased phosphorylation of downstream substrates such as GSK-3, p70S6K, 4EBP-1, and FKHR. Treatment with nicotine or NNK attenuated apoptosis caused by etoposide, ultraviolet irradiation, or hydrogen peroxide and partially induced a transformed phenotype manifest as loss of contact inhibition and loss of dependence on exogenous growth factors or adherence to ECM. In vivo, active Akt was detected in airway epithelial cells and lung tumors from NNK-treated A/J mice, and in human lung cancers derived from smokers. Redundant Akt activation by nicotine and NNK could contribute to tobacco-related carcinogenesis by regulating two processes critical for tumorigenesis, cell growth and apoptosis

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

“…These findings suggest that the G 12/13 96 and G i 97 signaling pathways are involved, respectively, and provide biochemical evidence of the hyperactive state of platelets. These data are also consistent with previous studies in which both the Akt98 and ERK99, 100 pathways were upregulated by nicotine.…”

Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer

“…In this issue of the JCI, Brognard and colleagues have extended these results by presenting intriguing findings concerning the activation of the Akt signaling pathway by nicotine and NNK in cultured lung epithelial cells (11). Using short-term cultures of large (normal human bronchial epithelial cells [NHBEs]), and small airway epithelial cells (SAECs) they showed that stimulation with nicotine and NNK in pharmacologically relevant concentrations (in the 100 nM range which is attained in the plasma of smokers) induced phosphorylation of Akt on physiologically relevant serine and threonine residues within minutes.…”

“…As with every good study, the report by Brognard et al (11) suggests a variety of questions and further experiments. Which cells in the bronchial epithelium express nAchRs and which of these cells develop activated Akt?…”

Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer

“…Using short-term cultures of large (normal human bronchial epithelial cells [NHBEs]), and small airway epithelial cells (SAECs) they showed that stimulation with nicotine and NNK in pharmacologically relevant concentrations (in the 100 nM range which is attained in the plasma of smokers) induced phosphorylation of Akt on physiologically relevant serine and threonine residues within minutes. In addition, increased Akt phosphorylation was detected in vivo in the lungs of NNK treated mice and in human lung cancers arising in smokers (11). Akt located at 14q32.3 in humans and sometimes called protein kinase B ([PKB] Online Mendelian Inheritance in Man no.…”

“…nAchR subtype, target cell differences, and other mechanisms by which nicotine could block apoptosis Brognard tion with nicotine or NNK (11). Specific nAchR antagonists were used to show that the α3 or α4 subtypes of nAchRs mediated the nicotine effect, while α7-containing nAchRs mediated the NNK effect.…”