Abstract 2268: Augmentation of DR5 expression by calmodulin antagonists sensitizes TRA-8-induced apoptosis in pancreatic cancer

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer death in the USA. The 5-year survival rate has only improved from 2% to 6% in the past 35 years. TNF-related apoptosis-inducing ligand (TRAIL) or agonistic antibodies bind to death receptor 4 or 5 and induce apoptosis in a wide variety of tumors. TRA-8, a humanized activating antibody for the death receptor 5 (DR5), is a potent apoptosis-inducing reagent for cancer cells. However, several pancreatic cell lines are resistant to TRA-8-induced apoptosis. The goal of our studies is to indentify therapeutic agents that sensitize resistant pancreatic cancer cells to TRA-8-induced apoptosis and determine the underlying mechanism. Among an array of compounds, we identified that trifluoperazine (TFP) and tamoxifen (TMX), two calmodulin (CaM) antagonists, enhanced TRA-8-induced cell death of TRA-8 resistance pancreatic cells. Both TFP and TMX increased TRA-8-induced apoptosis of resistant PANC-1 cells in dose-dependent manners. TMX treatment enhanced the efficacy of TRA-8 therapy on tumorigenesis of PANC-1 cells in a mouse xenograft model by 5 fold (n=7, p<0.05). We found that the effects of CaM antagonists on TRA-8-induced apoptosis were mediated by its induction of caspase-8 activation, as TMX increased TRA-8-induced activation of caspase-8 in the DR5-recruited signaling complex whereas caspase-8 inhibition by Z-IETD-FMK markedly decreased TRA-8-induced apoptosis as well as activation of downstream apoptosis effector caspase-3. Analysis of the expression of the death receptors revealed that TFP and TMX increased the expression of the DR5, at both mRNA and protein levels. Furthermore, TFP and TMX increased acetylation of histone H3 and H4, which may contribute their augmentation of DR5 expression. In summary, we have demonstrated that CaM antagonists increase DR5 expression and DR5-mediated caspase-8 activation, thus sensitizing pancreatic cancer to TRA 8-induced apoptosis. Our results identify an important role for CaM in regulating of DR5-mediated apoptosis signals in pancreatic cancer cells and support the possible use of combined TRA-8 and CaM antagonists to treat pancreatic cancer. Citation Format: Kaiyu Yuan, Tong Zhou, Jay McDonald, Yabing Chen. Augmentation of DR5 expression by calmodulin antagonists sensitizes TRA-8-induced apoptosis in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2268. doi:10.1158/1538-7445.AM2014-2268