Nicotine induces cell proliferation by β-arrestin–mediated activation of Src and Rb–Raf-1 pathways
Piyali Dasgupta, … , Eric Haura, Srikumar Chellappan
Piyali Dasgupta, … , Eric Haura, Srikumar Chellappan
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2208-2217. https://doi.org/10.1172/JCI28164.
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Research Article Oncology

Nicotine induces cell proliferation by β-arrestin–mediated activation of Src and Rb–Raf-1 pathways

Abstract

Recent studies have shown that nicotine, a component of cigarette smoke, can stimulate the proliferation of non-neuronal cells. While nicotine is not carcinogenic by itself, it has been shown to induce cell proliferation and angiogenesis. Here we find that mitogenic effects of nicotine in non–small cell lung cancers (NSCLCs) are analogous to those of growth factors and involve activation of Src, induction of Rb–Raf-1 interaction, and phosphorylation of Rb. Analysis of human NSCLC tumors show enhanced levels of Rb–Raf-1 complexes compared with adjacent normal tissue. The mitogenic effects of nicotine were mediated via the α7-nAChR subunit and resulted in enhanced recruitment of E2F1 and Raf-1 on proliferative promoters in NSCLC cell lines and human lung tumors. Nicotine stimulation of NSCLC cells caused dissociation of Rb from these promoters. Proliferative signaling via nicotinic acetylcholine receptors (nAChRs) required the scaffolding protein β-arrestin; ablation of β-arrestin or disruption of the Rb–Raf-1 interaction blocked nicotine-induced proliferation of NSCLCs. Additionally, suppression of β-arrestin also blocked activation of Src, suppressed levels of phosphorylated ERK, and abrogated Rb–Raf-1 binding in response to nicotine. It appears that nicotine induces cell proliferation by β-arrestin–mediated activation of the Src and Rb–Raf-1 pathways.

Authors

Piyali Dasgupta, Shipra Rastogi, Smitha Pillai, Dalia Ordonez-Ercan, Mark Morris, Eric Haura, Srikumar Chellappan

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Figure 5

Schematic depicting the proliferative signaling by nAChRs in NSCLC cells.

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Schematic depicting the proliferative signaling by nAChRs in NSCLC cells...
(A) Quiescent NSCLC cells do not display any association among β-arrestin, Src, and nAChRs. Rb is hypophosphorylated in these resting cells and is associated with E2F transcription factors. Quiescent cells do not show any binding between Raf-1 and Rb. E2F is present on the proliferative promoters but is repressed by Rb. (B) Nicotine stimulation causes the assembly of oligomeric complexes involving β-arrestin, Src, and nAChRs, facilitating the activation of Src. This leads to the activation of Raf-1, which binds to Rb; activation of MAPK and cyclins/cdks also occurs. The activation of Src facilitates the binding of Raf-1 to Rb, and multimeric complexes containing Rb, Raf-1, and E2F1 occupy proliferative promoters. Sustained mitogenic signaling leads to the dissociation of Raf-1 and Rb, while E2F remains bound to the proliferative promoters facilitating S-phase entry. Ablation of α7-nAChR subunits and β-arrestin–1, inhibition of Src activation, and disruption of the Rb–Raf-1 interaction all blocked nicotine-induced proliferation of NSCLC cells. TS, thymidylate synthase.