title: Fenretinide up-regulates DR5/TRAIL-R2 expression via the induction of the transcription factor CHOP and combined treatment with fenretinide and TRAIL induces synergistic apoptosis in colon cancer cell lines.
abstract: Fenretinide (N-[4-Hydroxyphenyl]retinamide; 4HPR) is a semisynthetic retinoid that induces apoptosis in a variety of malignancies. Fenretinide has been examined in clinical trials as a cancer chemopreventive and chemotherapeutic agent. Oxidative stress induced by fenretinide has been shown to mediate apoptosis through a mitochondrial pathway by the induction of a transcription factor CCAAT/enhancer binding protein homologous protein (CHOP) and Bak. In this study, we report that fenretinide induces death receptor 5 (DR5)/TRAIL-R2 up-regulation via the induction of the transcription factor CHOP in colon cancer cell lines. Fenretinide induced DR5 expression at protein and mRNA levels. Furthermore, fenretinide increased DR5 promoter activity and the enhanced activity decreased by mutation of the CHOP binding site. CHOP was also up-regulated by fenretinide at the promoter level. We also showed that combined treatment with fenretinide and TRAIL induced synergistic apoptosis in colon cancer cell lines. The synergistic apoptosis was markedly blocked by DR5/Fc chimeric protein. Fenretinide and TRAIL cooperatively activated caspase-3, -8, -10 and -9 and cleavage of Bid and PARP, and this activation was also blocked in the presence of DR5/Fc chimeric protein. These results indicate that fenretinide-induced apoptosis is sensitized by TRAIL. Therefore, combined treatment with fenretinide and TRAIL might be a promising model for the treatment of colorectal cancer.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kouhara
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakata
authors.forename: Mano
authors.initials: M
authors.lastname: Horinaka
authors.forename: Miki
authors.initials: M
authors.lastname: Wakada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ueda
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Yamagishi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004789:Enzyme Activation; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; D017313:Fenretinide; D020169:Caspases