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25600647
β-arrestin-1 mediates nicotine-induced metastasis through E2F1 target genes that modulate epithelial-mesenchymal transition.

Cancer Res, 2015/3/15;75(6):1009-20.

Pillai S[1], Trevino J[2], Rawal B[3], Singh S[4], Kovacs M[1], Li X[5], Schell M[6], Haura E[5], Bepler G[7], Chellappan S[8]

Affiliations

PMID: 25600647DOI: 10.1158/0008-5472.CAN-14-0681

Impact factor: 13.312

Abstract
Cigarette smoking is a major risk factor in the development of non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the major addictive component of tobacco smoke, can induce proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) in NSCLC cell lines and promote metastasis of NSCLC in mice. Here, we demonstrate that the scaffolding protein β-arrestin-1 is necessary for nicotine-mediated induction of mesenchymal genes vimentin and fibronectin as well as EMT regulators ZEB1 and ZEB2. Nicotine induced changes in cell morphology and ablate tight junctions consistent with EMT; β-arrestin-1, but not β-arrestin-2, was required for these changes. β-Arrestin-1 promoted the expression of the mesenchymal genes, as well as ZEB1 and ZEB2, through the mediation of the E2F1 transcription factor; this required Src kinase activity. Stimulation of multiple NSCLC cell lines with nicotine led to enhanced recruitment of β-arrestin-1 and E2F1 on vimentin, fibronectin, and ZEB1 and ZEB2 promoters. Furthermore, there was significantly more β-arrestin-1 and E2F1 associated with these promoters in human NSCLC tumors, and β-arrestin-1 levels correlated with vimentin and fibronectin levels in human NSCLC samples. A549-luciferase cells lacking β-arrestin-1 showed a significantly reduced capacity for tumor growth and metastasis when orthotopically implanted into the lungs of SCID-beige mice. Taken together, these studies reveal a novel role for β-arrestin-1 in the growth and metastasis of NSCLC.
MeSH terms
Animals; Arrestins; Cell Line, Tumor; E2F1 Transcription Factor; Epithelial-Mesenchymal Transition; Fibronectins; Homeodomain Proteins; Humans; Lung Neoplasms; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Nicotine; Receptors, Nicotinic; Retinoblastoma Protein; Signal Transduction; Tight Junctions; Transcription Factors; Vimentin; Zinc Finger E-box-Binding Homeobox 1; beta-Arrestin 1; beta-Arrestin 2; beta-Arrestins
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