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J. Biol. Chem., Vol. 279, Issue 21, 22138-22144, May 21, 2004

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p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D Receptor^*

Xiaomei Qi, Jun Tang, Rocky Pramanik, Richard M. Schultz¶, Senji Shirasawa||, Takehiko Sasazuki||, Jiahuai Han**, and Guan Chen

From the Department of Radiation Oncology, Program in Molecular and Cellular Biochemistry and Program in Molecular Biology and the ^¶Department of Cell Biology, Neurobiology, and Anatomy, Loyola University of Chicago, Maywood, Illinois 05163, the ^||Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo 162-8655, Japan, and the ^**Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

ras is the most characterized oncogene in human cancer, and yet there are no effective therapeutics to selectively target this oncogene. Our previous work demonstrated the inhibitory activity of the p38 pathway in Ras proliferative signaling in experimental NIH 3T3 cells (Chen, G., Hitomi, M., Han, J., and Stacey, D. W. (2000) J. Biol. Chem. 275, 38973-38980). Here we explore the therapeutic potential of p38 kinase activation in human colon cancer cells with and without endogenous K-ras activation. p38 activation by both adenovirus-mediated gene delivery of constitutively active p38 activator MKK6 and by arsenite selectively induces cell death in K-ras-activated human colon cancer HCT116 cells but not in the K-ras-disrupted HCT116-derived sublines. The cell death-inducing effect of MKK6 is not because of its selective activation of p38 kinase or its downstream transcription factor substrates, ATF-2 or c-Jun, in K-ras-activated cells. Rather, cell death in K-ras-activated cells is linked to the down-regulation of vitamin D receptor (VDR) by an AP-1-dependent mechanism. Forced VDR expression in K-ras-activated cells inhibits p38 activation-induced cell death, and inhibition of endogenous VDR protein expression in K-ras-disrupted cells increased the arsenite-induced toxicity. Analysis of an additional two human colon cancer cell lines with and without K-ras mutation also showed a K-ras- and VDR-dependent toxicity of MKK6. Hence, p38 pathway activation selectively induces cell death in K-ras-mutated human colon cancer cells by mechanisms involving the suppression of VDR activity.

Received for publication, December 22, 2003 , and in revised form, February 11, 2004.

^* This study was supported by National Institutes of Health Grant CA91576 (to G. C.). 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: Dept. of Radiation Oncology, Loyola University of Chicago, 114B-Bldg.1, B303 (Hines), 2160 S. First Ave., Maywood, IL 60153. Tel.: 708-202-5762; Fax: 708-202-2019; E-mail: gchen1{at}lumc.edu.

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