Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers

Abstract

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 β-adrenergic receptors (β-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 α7-nAChRs, with possible contribution from the β-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-(3-pyridyl)-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 β-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.

Figure 1

Schematic representation of cooperative receptor crosstalk upon nicotine stimulation. Components of tobacco smoke induce nAChR signaling, which in turn activates additional cell surface receptors such as β-AR and EGFR, stimulating tumor promoting signaling cascades. In addition, upon NNK or nicotine binding, nAChRs are activated stimulating the secretion of growth factors such as EGF which activate EGFRs, as well as neurotrophic factors such as adrenaline and noradrenaline which bind to and activate β-ARs. Upon activation, β-ARs further stimulate secretion of EGF to further transactivate EGFRs. This receptor crosstalk suggests a cooperative interaction that facilitates tobacco induced cancer progression.

Figure 2

A schematic representing nAChR signaling cascades in lung cancer. NNK and nicotine found in tobacco smoke bind to nAChRs with high affinity and induce multiple signaling cascades resulting in cycle progression, proliferation, and survival. Upon activation of nAChRs by ligand binding, β-arrestin-1 is recruited to the receptor and is necessary for further recruitment of Src kinase, which in turn initiates Raf-1 and PI3K/AKT signaling cascades. NNK and nicotine mediated nAChR activation have also been shown to induce signaling cascades such as JAK/STAT and Ras/Raf/MAPK, and decrease the levels of cell cycle inhibitors like p16INK4 and Cip/Kip proteins.