Faculty Collaboration Database

p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor. J Biol Chem 2004 May 21;279(21):22138-44

Date

03/24/2004

Pubmed ID

15037631

DOI

10.1074/jbc.M313964200

Scopus ID

2-s2.0-2542458262 (requires institutional sign-in at Scopus site)   60 Citations

Abstract

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.

Author List

Qi X, Tang J, Pramanik R, Schultz RM, Shirasawa S, Sasazuki T, Han J, Chen G

Authors

Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Xiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenoviridae
Arsenites
Blotting, Western
Calcium-Calmodulin-Dependent Protein Kinases
Cell Death
Cell Line, Tumor
Colonic Neoplasms
DNA, Complementary
Down-Regulation
Enzyme Activation
Gene Expression Regulation, Neoplastic
Genes, ras
Humans
Luciferases
MAP Kinase Kinase 6
Mitogen-Activated Protein Kinases
Models, Biological
Mutation
Promoter Regions, Genetic
RNA, Small Interfering
Receptors, Calcitriol
Signal Transduction
Transcription Factor AP-1
Transfection
p38 Mitogen-Activated Protein Kinases