Abstract
Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAIL-R1) also known as death receptor 4 (DR4), is a death domain containing transmembrane receptor involved in TRAIL-mediated apoptosis. One biological function of retinoic acid (RA) among many others is to regulate apoptosis, in part through TRAIL induction. The current study reveals another novel mechanism by which RA modulates apoptosis. For the first time, we found that RA increased TRAIL-R1 expression in various types of human cancer cell lines; this effect could be abrogated by the transcriptional inhibitor actinomycin-D. Moreover, RA increased TRAIL-R1 mRNA level and transactivated its promoter. These data collectively indicate that RA induces TRAIL-R1 expression at the transcriptional level. We also found that RA-induced TRAIL-R1 expression could be abolished by some retinoic acid receptor (RAR) antagonists, whereas various RAR agonists upregulated TRAIL-R1 expression, suggesting that RA induces a RAR-dependent TRAIL-R1 expression. Importantly, we identified two putative RA responsive elements (RARE) named RARE-Pal17 (a palindrome separated by 17 bases) and RARE-DR11 (a direct repeat separated by 11 bases) in the 5′ flanking region of TRAIL-R1 gene. Deletion and mutation of RARE-DR11, but not RARE-Pal17, abrogated RA's effect on transactivation of TRAIL-R1 promoter. In agreement, ChIP assay detected only RARE-DR11 binding, but not RARE-Pal17 binding, in RA-treated cells. These data collectively indicate that the RARE-DR11 is an active one that is responsible for TRAIL-R1 gene transactivation by RA. Furthermore, RA, when combined with TRAIL or agonistic anti-TRAIL-R1 antibody, augmented apoptosis in cancer cells. Taken together, the current study provides compelling evidence that TRAIL-R1 is a RAR target gene and mediates modulation of death receptor-induced apoptosis by RA, thus highlighting a novel mechanism by which RA modulates apoptosis.(SSR, FRK and SYS are Georgia Cancer Coalition Distinguished Cancer Scholars. This study was supported by funds from the Georgia Cancer Coalition Distinguished Cancer Scholar, NIH Head and Neck SPORE P50 CA128613 and DOD VITAL awards) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-335.
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