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Papers In Press, published online ahead of print March 22, 2004
Department of Radiation Oncology, Loyola University of Chicago, Maywood, IL 60153
Corresponding Author: gchen1{at}lumc.edu
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 (ARS) 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 due to 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 ARS-induced toxicity. Analysis of 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.
J. Biol. Chem, 10.1074/jbc.M313964200
Submitted on December 22, 2003
Revised on February 11, 2004
Accepted on March 22, 2004
p38 MAPK activation selectively induces cell death in K-ras mutated human colon cancer cells through regulation of vitamin D receptor
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