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J. Biol. Chem., Vol. 279, Issue 51, 53683-53690, December 17, 2004

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Tobacco-specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induces Phosphorylation of µ- and m-Calpain in Association with Increased Secretion, Cell Migration, and Invasion^*

Lijun Xu and Xingming Deng

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

Mounting evidence indicates that cigarette smoking not only promotes tumorigenesis but also may increase the spread of cancer cells in the body. However, the intracellular mechanism(s) by which cigarette smoking promotes metastasis of human lung cancer remains enigmatic. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an important component in cigarette smoke and is formed by nitrosation of nicotine. µ- and m-calpain (calpain I and calpain II) are major members of the calpain family, which are ubiquitously expressed in both small cell lung cancer and non-small cell lung cancer cells. Our findings indicated that NNK potently induces phosphorylation of both µ- and m-calpain in association with their activation and increased migration as well as invasion of lung cancer cells. Treatment of cells with PD98059 blocked phosphorylation of m- and µ-calpain and resulted in suppression of NNK-induced cell migration and invasion. p44 MAPK/extracellular signal-regulated kinase 1 (ERK1) and p42 MAPK/ERK2 were activated by NNK, co-localized with µ- and m-calpain in cytoplasm, and directly phosphorylated µ- and m-calpain in vitro. These findings suggest a role for the ERK1/2 kinases as NNK-activated physiological calpain kinases. Specific knock-down of µ- and/or m-calpain expression by RNA interference blocked NNK-stimulated migration and invasion, suggesting that µ- and m-calpain may act as required targets in a NNK-induced metastatic signaling pathway. Furthermore, NNK promotes secretion of active µ- and m-calpain from lung cancer cells through vesicles, which may have the potential to cleave substrates in the extracellular matrix. Thus, NNK-induced cell migration and invasion may occur, at least in part, through a novel mechanism involving phosphorylation of calpains that leads to their activation and secretion, which may contribute to metastasis and/or progression of lung cancer.

Received for publication, August 27, 2004

^* This work was supported by a Flight Attendant Medical Research Institute Clinical Innovator Award and a start-up fund from the University of Florida Shands Cancer Center (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.

To whom correspondence should be addressed: University of Florida Shands Cancer Center, 1600 S.W. 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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