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PMID: 16862215 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

The Journal of clinical investigation ·Vol. 116 ·No. 8 ·2006-08-00 ·Pages 2208-2217

Dasgupta P, Rastogi S, Pillai S, Ordonez-Ercan D, Morris M, Haura E, Chellappan S

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 alpha7-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 beta-arrestin; ablation of beta-arrestin or disruption of the Rb-Raf-1 interaction blocked nicotine-induced proliferation of NSCLCs. Additionally, suppression of beta-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 beta-arrestin-mediated activation of the Src and Rb-Raf-1 pathways.

MeSH Terms
Arrestins/physiology Carcinoma, Non-Small-Cell Lung/pathology Cell Division/drug effects Cell Line Cell Line, Tumor Enzyme Activation Humans Lung Neoplasms/pathology Nicotine/pharmacology Promoter Regions, Genetic Proto-Oncogene Proteins c-raf/metabolism Receptors, Nicotinic/drug effects,physiology Retinoblastoma Protein/antagonists & inhibitors,drug effects,metabolism beta-Arrestins src-Family Kinases/metabolism
Chemicals
Arrestins Receptors, Nicotinic Retinoblastoma Protein beta-Arrestins Nicotine src-Family Kinases Proto-Oncogene Proteins c-raf
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Dasgupta Piyali
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa 33612, USA.
Rastogi Shipra
Pillai Smitha
Ordonez-Ercan Dalia
Morris Mark
Haura Eric
Chellappan Srikumar
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI28164
Published
2006-08-00
Pages
2208-2217
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1513051
Subset
IM
Grants
NCI NIH HHS · R01 CA063136 · United States
NCI NIH HHS · CA63136 · United States
External Links
PubMed source DOI: 10.1172/JCI28164 PMC Full Text View journal details
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