Retinoic acid enhances TRAIL induced apoptosis in cancer cells by upregulating TRAIL receptor 1 expression

• Type of Material: Article
• Authors: Latha Dhandapani, Emory University; Ping Yue, Emory University; Suresh S Ramalingam, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2011-08-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2011 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158%2F0008-5472.CAN-10-4180
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 71
• Issue: 15
• Start Page: 5245
• End Page: 5254
• Grant/Funding Information: Grant Support: Georgia Cancer Coalition Distinguished Cancer Scholar award (to S-Y. Sun), Department of Defense grant W81XWH-04-1-0142-VITAL (to S-Y. Sun for Project 4) and NIH/NCI SPORE P50 grant CA128613 (to S-Y. Sun for Project 2).
• Keywords: TRAIL receptor 1; retinoic acid receptors (RARs); apoptosis; Retinoic acid
• Research Categories: Health Sciences, Oncology; Biology, Microbiology

Abstract

Many human cancer cells are sensitive to killing by the pro-apoptotic ligand TRAIL which is under study for cancer treatment in clinical trials. The TRAIL receptor TRAIL-R1 (also known as DR4) is a transmembrane receptor that mediates TRAIL-induced apoptosis in cancer cells. In this study, we show that retinoids sensitize cancer cells to TRAIL-induced apoptosis by upregulating expression of TRAIL-R1. All-trans retinoic acid (ATRA) upregulated TRAIL-R1 expression in human cancer cells at the transcriptional level. The ability of ATRA to activate TRAIL-R1 expression was inhibited by retinoic acid receptor (RAR) antagonists or small interfering RNAs, but augmented by several RAR agonists. In analyzing how ATRA induces RAR-dependent transcriptional upregulation of TRAIL-R1 we identified two putative RA response elements (RARE) termed Pal-17 (a palindrome separated by 17 bases) and DR-11 (a direct repeat separated by 11 bases) in the 5′ flanking region of TRAIL-R1 gene. Deletion of DR-11 but not Pal-17 abrogated the ability of ATRA to stimulate TRAIL-R1 promoter activity. Consistent with this observation, RAR binding to DR-11 but not to Pal-17 was detected by ChIP assay in ATRA-treated cells, arguing that DR-11 was responsible for ATRA-mediated activation of the TRAIL-R1 gene. ATRA augmented TRAIL-induced apoptosis of cancer cells and this activity was attenuated by a blockade to upregulation of TRAIL-R1 expression. Taken together, our findings establish that ATRA accentuates TRAIL-induced apoptosis, reveal a novel mechanism by which retinoids modulate apoptosis, and suggest a novel strategy to augment the anti-cancer activity of TRAIL.