Journal
MOLECULAR CANCER RESEARCH
Volume 12, Issue 1, Pages 14-23Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-13-0541
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Funding
- NCI [CA127725, CA139612]
- NATIONAL CANCER INSTITUTE [R01CA127725, R01CA139612] Funding Source: NIH RePORTER
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Tobacco smoke contains multiple classes of established carcinogens including benzo(a) pyrenes, polycyclic aromatic hydrocarbons, and tobacco-specific nitrosamines. Most of these compounds exert their genotoxic effects by forming DNA adducts and generation of reactive oxygen species, causing mutations in vital genes such as K-Ras and p53. In addition, tobacco-specific nitrosamines can activate nicotinic acetylcholine receptors (nAChR) and to a certain extent beta-adrenergic receptors (beta-AR), promoting cell proliferation. Furthermore, it has been demonstrated that nicotine, the major addictive component of tobacco smoke, can induce cell-cycle progression, angiogenesis, and metastasis of lung and pancreatic cancers. These effects occur mainly through the alpha 7-nAChRs, with possible contribution from the beta-ARs and/or epidermal growth factor receptors. This review article will discuss the molecular mechanisms by which nicotine and its oncogenic derivatives such as 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone and N-nitrosonornicotine induce cell-cycle progression and promote tumor growth. A variety of signaling cascades are induced by nicotine through nAChRs, including the mitogen-activated protein kinase/ extracellular signal-regulated kinase pathway, phosphoinositide 3-kinase/AKT pathway, and janus-activated kinase/STAT signaling. In addition, studies have shown that nAChR activation induces Src kinase in a beta-arrestin-1-dependent manner, leading to the inactivation of Rb protein and resulting in the expression of E2F1-regulated proliferative genes. Such nAChR-mediated signaling events enhance the proliferation of cells and render them resistant to apoptosis induced by various agents. These observations highlight the role of nAChRs in promoting the growth and metastasis of tumors and raise the possibility of targeting them for cancer therapy. (C) 2014 AACR.
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