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Coupling of Endoplasmic Reticulum Stress to CDDO-Me–Induced Up-regulation of Death Receptor 5 via a CHOP–Dependent Mechanism Involving JNK Activation

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Shi-Yong Sun, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road Northeast, C3088, Atlanta, GA 30322. Phone: 404-778-2170; Fax: 404-778-5520; E-mail: ssun{at}emory.edu.

Key Words: CDDO-Me • ER stress • CHOP • death receptor 5 • JNK • apoptosis

The synthetic triterpenoid methyl-2-cyano-3,12-dioxoolean-1,9-dien-28-oate (CDDO-Me) is in phase I clinical trials as a novel cancer therapeutic agent. We previously showed that CDDO-Me induces c-Jun NH₂-terminal kinase (JNK)–dependent death receptor 5 (DR5) expression and augments death receptor–induced apoptosis. The current study focused on addressing how CDDO-Me induces JNK-dependent DR5 expression. Analysis of DR5 promoter regions defines that the CCAAT/enhancer binding protein homologous protein (CHOP) binding site is responsible for CDDO-Me–induced transactivation of the DR5 gene. Consistently, CDDO-Me induced DR5 expression and parallel CHOP up-regulation. Blockade of CHOP up-regulation also abrogated CDDO-Me–induced DR5 expression. These results indicate that CDDO-Me induces CHOP-dependent DR5 up-regulation. Moreover, the JNK inhibitor SP600125 abrogated CHOP induction by CDDO-Me, suggesting a JNK-dependent CHOP up-regulation by CDDO-Me as well. Importantly, knockdown of CHOP attenuated CDDO-Me–induced apoptosis, showing that CHOP induction is involved in CDDO-Me–induced apoptosis. Additionally, CDDO-Me increased the levels of Bip, phosphorylated eukaryotic translation initiation factor 2, inositol requiring kinase 1, and activating transcription factor 4, all of which are featured changes during endoplasmic reticulum (ER) stress. Furthermore, salubrinal, an inhibitor of ER stress–induced apoptosis, inhibited JNK activation and up-regulation of CHOP and DR5 by CDDO-Me and protected cells from CDDO-Me–induced apoptosis. Thus, ER stress seems to be important for CDDO-Me–induced JNK activation, CHOP and DR5 up-regulation, and apoptosis. Collectively, we conclude that CDDO-Me triggers ER stress, leading to JNK-dependent, CHOP-mediated DR5 up-regulation and apoptosis. [Cancer Res 2008;68(18):7484–92]