Proteasome Inhibitor MG132 Induces Death Receptor 5 through CCAAT/Enhancer-Binding Protein Homologous Protein

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 À289 to À253. 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 upregulation. 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. (Cancer Res 2005; 65(13): 5662-7)

Acrolein sensitizes human renal cancer Caki cells to TRAIL-induced apoptosis via ROS-mediated up-regulation of death receptor-5 (DR5) and down-regulation of Bcl-2

“…4D). Consistent with our findings, MG132 (proteasome inhibitor) and triterpenoid also induced DR5 up-regulation through CHOP protein [40,41].…”

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

“…3A), suggesting that Wit A modulates DR5 expression at the transcriptional level. Recently, CHOP was shown to be involved in MG132-or tunicamycin-mediated DR5 upregulation, contributing to the sensitization of TRAIL-mediated apoptosis [14,15]. We found that the protein level of CHOP was significantly increased by Wit A treatment in a dose-dependent manner, but KDEL (Lys-Asp-Glu-Leu), an ER stress marker protein, was not altered (Fig.…”

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

“…CHOP is a pivotal transcription factor involved in apoptosis induced by diverse stimuli including, DNA damage and chemotherapeutic agents [35]. We observed that emodin treatment induced the expression of CHOP and the knockdown of CHOP gene using the siRNA inhibited the effect of emodin on the induction of death receptors and on the TRAIL-induced apoptosis, thereby implicating the critical role of CHOP in mediating the apoptotic effects of emodin.…”

“…Emodin-induced up-regulation of DR5 is mediated through induction of CHOP Because CHOP has been linked with the up-regulation of DR5 expression [35]; we next examined the role of CHOP in emodin-induced DR5 up-regulation. Our results showed that emodin induced the expression of CHOP, with optimal induction occurring around 16-24 h (Fig.…”