Downregulation of Stem-Loop Binding Protein by Nicotine via α7-Nicotinic Acetylcholine Receptor and Its Role in Nicotine-Induced Cell Transformation

Abstract

The use of electronic-cigarettes (e-cigs) has increased substantially in recent years, particularly among the younger generations. Liquid nicotine is the main component of e-cigs. Previous studies have shown that mice exposed to e-cig aerosols developed lung adenocarcinoma and bladder hyperplasia. These findings implicated a potential role for e-cig aerosols and nicotine in cancer development, although the underlying mechanisms are not fully understood. Here we report that exposure to liquid nicotine or nicotine aerosol generated from e-cig induces downregulation of Stem-loop binding protein (SLBP) and polyadenylation of canonical histone mRNAs in human bronchial epithelial cells and in mice lungs. Canonical histone mRNAs typically do not end in a poly(A) tail and the acquisition of such a tail via depletion of SLBP has been shown to causes chromosome instability. We show that nicotine-induced SLBP depletion is reversed by an inhibitor of α7-nicotinic acetylcholine receptors (α7-nAChR) or siRNA specific for α7-nAChR, indicating a nAChR-dependent reduction of SLBP by nicotine. Moreover, PI3K/AKT pathway is activated by nicotine exposure and CK2 and probably CDK1, two kinases well known for their function for SLBP phosphorylation and degradation, are shown to be involved, α7-nAChR-dependently, in nicotine-induced SLBP depletion. Importantly, nicotine-induced anchorage-independent cell growth is attenuated by inhibition of α7-nAChR and is rescued by overexpression of SLBP. We propose that the SLBP depletion and polyadenylation of canonical histone mRNAs via activation of α7-nAChR and a series of downstream signal transduction pathways, are critical for nicotine-induced cell transformation and potential carcinogenesis.

Nicotine: From Discovery to Biological Effects

“…[ [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] The biological effects of nicotine are diverse, and include both negative effects on the cardiovascular system and addiction (now classified as Substance Use Disorders) [2], as well as positive effects such as enhancing cognitive function in individuals with Alzheimer's disease [86]. A significant portion of the clinical phenotype observed in Alzheimer's disease (AD) occurs through nAChRs.…”

“…The availability of data regarding the genotoxic effects of nicotine, including sister chromatid exchange, chromosome aberration, and induction of DNA double-strand breaks in mammalian cells, is not yet sufficient [10][11][12][13]. On the other hand, as outlined in Section 2.4, the role of nicotine in cell proliferation, especially in tumor cells, is well documented, supporting the hypothesis of its role as a promoting agent in the process of human carcinogenesis [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31].…”