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Papers In Press, published online ahead of print December 16, 2005
Department of Medicine, University of Florida Shands Cancer Center, Gainesville, Florida 32610-0232
Corresponding Author: xdeng{at}ufscc.ufl.edu
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 mu- and m-calpains via activation of PKC iota, which is associated with accelerated migration and invasion of human lung cancer cells. Purified PKC iota directly phosphorylates mu- and m-calpains in vitro. Overexpression of PKC iota results in increased phosphorylation of both mu- and m-calpains in vivo. Nicotine also induces activation of c-Src which is a known PKC iota upstream kinase. Treatment of cells with the alpha7 nicotinic acetylcholine receptor inhibitor alpha-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 alpha7 nicotinic acetylcholine receptor. Intriguingly, depletion of PKC iota by RNA interference suppresses nicotine-induced calpain phosphorylation, calpain activity, cell migration and invasion, indicating that PKC iota is a necessary component in nicotine-mediated cell motility signaling. Importantly, nicotine potently induces secretion of mu- 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 iota as a nicotine-activated, physiological calpain kinase which directly phosphorylates and activates calpains leading to enhanced migration and invasion of human lung cancer cells.
J. Biol. Chem, 10.1074/jbc.M510721200
Submitted on September 30, 2005
Revised on December 2, 2005
Accepted on December 16, 2005
Protein kinase C
promotes nicotine-induced migration and invasion of cancer cells via phosphorylation of 
- and m-calpains
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