Proteasome inhibitor MG132 induces death receptor 5 through CCAAT/enhancer-binding protein homologous protein

Tatsushi Yoshida, Takumi Shiraishi, Susumu Nakata, Mano Horinaka, Miki Wakada, Yoichi Mizutani, Tsuneharu Miki, Toshiyuki Sakai

Research output: Contribution to journalArticlepeer-review

Abstract

Combined treatment with a proteasome inhibitor and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for cancer therapy. Proteasome inhibitors induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechaism of DR5 up-regulation has not been elucidated. In this study, we report that CCAAT/enhancer-binding protein homologous protein (CHOP) is a regulator of DR5 induction by proteasome inhibitor MG132. MG132 induced DR5 expression at a protein and mRNA level in prostate cancer DU145 cells. Furthermore, MG132 increased DR5 promoter activity. Using a series of deletion mutant plasmids containing DR5 promoters of various sizes, we found that MG132 stimulated the promoter activity via the region of -289 to -253. This region contained a CHOP-binding site. Site-directed mutation of the site abrogated the promoter activity enhanced by MG132. An electrophoretic mobility shift assay showed that CHOP directly bound to the MG132-responsive site on the DR5 promoter. Expression of the CHOP protein was increased with MG132 along with DR5 up-regulation. Furthermore, CHOP small interfering RNA attenuated the DR5 up-regulation due to MG132. These results indicate that the proteasome inhibitor MG132 induces DR5 expression through CHOP up-regulation.

Original languageEnglish (US)
Pages (from-to)5662-5667
Number of pages6
JournalCancer Research
Volume65
Issue number13
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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