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J. Biol. Chem., Vol. 281, Issue 7, 4457-4466, February 17, 2006

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Protein Kinase C Promotes Nicotine-induced Migration and Invasion of Cancer Cells via Phosphorylation of µ- and m-Calpains^*

From the University of Florida Shands Cancer Center, Departments of Medicine and of Anatomy and Cell Biology, University of Florida, Gainesville, Florida 32610-0232

Nicotine is a major component in cigarette smoke that activates the growth-promoting pathways to facilitate the development of lung cancer. However, it is not clear whether nicotine affects cell motility to facilitate tumor metastasis. Here we discovered that nicotine potently induces phosphorylation of both µ- and m-calpains via activation of protein kinase C (PKC), which is associated with accelerated migration and invasion of human lung cancer cells. Purified PKC directly phosphorylates µ- and m-calpains in vitro. Overexpression of PKC results in increased phosphorylation of both µ- and m-calpains in vivo. Nicotine also induces activation of c-Src, which is a known PKC upstream kinase. Treatment of cells with the ₇ nicotinic acetylcholine receptor inhibitor -bungarotoxin can block nicotine-induced calpain phosphorylation with suppression of calpain activity, wound healing, cell migration, and invasion, indicating that nicotine-induced calpain phosphorylation occurs, at least in part, through a signaling pathway involving the upstream ₇ nicotinic acetylcholine receptor. Intriguingly, depletion of PKC by RNA interference suppresses nicotine-induced calpain phosphorylation, calpain activity, cell migration, and invasion, indicating that PKC is a necessary component in nicotine-mediated cell motility signaling. Importantly, nicotine potently induces secretion of µ- and m-calpains from lung cancer cells into culture medium, which may have potential to cleave substrates in the extracellular matrix. These findings reveal a novel role for PKC as a nicotine-activated, physiological calpain kinase that directly phosphorylates and activates calpains, leading to enhanced migration and invasion of human lung cancer cells.

Received for publication, September 30, 2005 , and in revised form, December 2, 2005.

^* This work was supported by NCI, National Institutes of Health Grant R01CA112183-01 and a Flight Attendant Medical Research Institute Clinical Innovator Award (to X. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Florida Shands Cancer Center, 1600 SW Archer Rd., Academic Research Bldg., R4-216, P. O. Box 100232, Gainesville, FL 32610-0232. Tel.: 352-392-9232; Fax: 352-392-5802; E-mail: xdeng{at}ufscc.ufl.edu.

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