HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 279/21/22138    most recent M313964200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qi, X. Articles by Chen, G. Search for Related Content PubMed PubMed Citation Articles by Qi, X. Articles by Chen, G. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Macias-Perez, C. Borza, X. Chen, X. Yan, R. Ibanez, G. Mernaugh, L. M. Matrisian, R. Zent, and A. Pozzi Loss of Integrin {alpha}1{beta}1 Ameliorates Kras-Induced Lung Cancer Cancer Res., August 1, 2008; 68(15): 6127 - 6135. [Abstract] [Full Text] [PDF]

				X. Qi, N. M. Pohl, M. Loesch, S. Hou, R. Li, J.-Z. Qin, A. Cuenda, and G. Chen p38{alpha} Antagonizes p38{gamma} Activity through c-Jun-dependent Ubiquitin-proteasome Pathways in Regulating Ras Transformation and Stress Response J. Biol. Chem., October 26, 2007; 282(43): 31398 - 31408. [Abstract] [Full Text] [PDF]

				R. Lu, X. Wang, Z.-F. Chen, D.-F. Sun, X.-Q. Tian, and J.-Y. Fang Inhibition of the Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway Decreases DNA Methylation in Colon Cancer Cells J. Biol. Chem., April 20, 2007; 282(16): 12249 - 12259. [Abstract] [Full Text] [PDF]

				Q.-P. Li, X. Qi, R. Pramanik, N. M. Pohl, M. Loesch, and G. Chen Stress-induced c-Jun-dependent Vitamin D Receptor (VDR) Activation Dissects the Non-classical VDR Pathway from the Classical VDR Activity J. Biol. Chem., January 19, 2007; 282(3): 1544 - 1551. [Abstract] [Full Text] [PDF]

				X. Qi, J. Tang, M. Loesch, N. Pohl, S. Alkan, and G. Chen p38{gamma} Mitogen-Activated Protein Kinase Integrates Signaling Crosstalk between Ras and Estrogen Receptor to Increase Breast Cancer Invasion. Cancer Res., August 1, 2006; 66(15): 7540 - 7547. [Abstract] [Full Text] [PDF]

				N. Smakman, D. J. M. van den Wollenberg, I. H. M. B. Rinkes, R. C. Hoeben, and O. Kranenburg Sensitization to Apoptosis Underlies KrasD12-Dependent Oncolysis of Murine C26 Colorectal Carcinoma Cells by Reovirus T3D J. Virol., December 1, 2005; 79(23): 14981 - 14985. [Abstract] [Full Text] [PDF]

				J. Tang, X. Qi, D. Mercola, J. Han, and G. Chen Essential Role of p38{gamma} in K-Ras Transformation Independent of Phosphorylation J. Biol. Chem., June 24, 2005; 280(25): 23910 - 23917. [Abstract] [Full Text] [PDF]

				A. P. B. Dackiw, S. Ezzat, P. Huang, W. Liu, and S. L. Asa Vitamin D3 Administration Induces Nuclear p27 Accumulation, Restores Differentiation, and Reduces Tumor Burden in a Mouse Model of Metastatic Follicular Thyroid Cancer Endocrinology, December 1, 2004; 145(12): 5840 - 5846. [Abstract] [Full Text] [PDF]

				G. P. Collett and F. C. Campbell Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells Carcinogenesis, November 1, 2004; 25(11): 2183 - 2189. [Abstract] [Full Text] [PDF]