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, Guan Chen

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)22138-22144
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number21
DOIs
Publication statusPublished - May 21 2004
Externally publishedYes

Fingerprint

Calcitriol Receptors
p38 Mitogen-Activated Protein Kinases
Cell death
Colonic Neoplasms
Cell Death
Chemical activation
Cells
Oncogenes
Toxicity
Phosphotransferases
Activating Transcription Factors
HCT116 Cells
NIH 3T3 Cells
Transcription Factor AP-1
Adenoviridae
Transcription Factors
Down-Regulation
Genes
Cell Line
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor. / Qi, Xiaomei; Tang, Jun; Pramanik, Rocky; Schultz, Richard M.; Shirasawa, Senji; Sasazuki, Takehiko; Han, Jiahuai; Chen, Guan.

In: Journal of Biological Chemistry, Vol. 279, No. 21, 21.05.2004, p. 22138-22144.

Research output: Contribution to journalArticle

Qi, Xiaomei ; Tang, Jun ; Pramanik, Rocky ; Schultz, Richard M. ; Shirasawa, Senji ; Sasazuki, Takehiko ; Han, Jiahuai ; Chen, Guan. / p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 21. pp. 22138-22144.
@article{d80c37e55d4349698139fa71884893b0,
title = "p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor",
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 = "Xiaomei Qi and Jun Tang and Rocky Pramanik and Schultz, {Richard M.} and Senji Shirasawa and Takehiko Sasazuki and Jiahuai Han and Guan Chen",
year = "2004",
month = "5",
day = "21",
doi = "10.1074/jbc.M313964200",
language = "English",
volume = "279",
pages = "22138--22144",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "21",

}

TY - JOUR

T1 - p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor

AU - Qi, Xiaomei

AU - Tang, Jun

AU - Pramanik, Rocky

AU - Schultz, Richard M.

AU - Shirasawa, Senji

AU - Sasazuki, Takehiko

AU - Han, Jiahuai

AU - Chen, Guan

PY - 2004/5/21

Y1 - 2004/5/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=2542458262&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2542458262&partnerID=8YFLogxK

U2 - 10.1074/jbc.M313964200

DO - 10.1074/jbc.M313964200

M3 - Article

C2 - 15037631

AN - SCOPUS:2542458262

VL - 279

SP - 22138

EP - 22144

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -