Pancreatic cancer is a highly malignant tumor with limited therapy and poor prognosis. Activation of death receptors (DR)-induced apoptotic pathways using antibodies or agonists for the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy. However, most pancreatic tumors are resistant to TRAIL therapy. The present studies aimed to identify combination therapies that enhance the efficacy of TRAIL therapy by sensitizing resistant pancreatic cancer cells to TRAIL-induced apoptosis, and to investigate the underlying mechanisms.

Using TRA-8, a monoclonal agonistic antibody specific for DR5, we demonstrated that TRA-8 induced apoptosis of 60% and 83% of BxPc-3 and MiaPaCa-2 pancreatic cancer cells in 24 hours. By contrast, only 20% and 24% of PANC-1 and Suit-2 cells underwent apoptosis in response to TRA-8 (n=3), despite the fact that they express high levels of the DR5 receptor. The expression of poly(ADP-ribose) polymerase-1 (PARP-1) was higher in the PANC-1 and Suit-2 cells than that BxPc-3 and MiaPaCa-2 cells, which may contribute to their resistance to TRA-8-induced apoptosis. Inhibition of PARP-1 with a pharmacologic inhibitor (PJ-34) sensitized PANC-1 to TRA-8 induced apoptosis in a dose-dependent manner. Furthermore, small interfering RNAs specifically knocking down PARP-1 in PANC-1 cells enhanced TRA-8-induced apoptosis in vitro by 2.5 fold, as well as the efficacy of TRA-8 therapy on tumorigenesis of PANC-1 cells in a mouse xenograft model by 3.8 fold (n=8, p<0.01). PARP-1 knockdown increased TRA-8-induced activation of caspase-8 in the death-induced signaling complex (DISC). Immuoprecipitation with DR5 antibody identified the recruitment of PARP-1 and PARP1-mediated protein poly-ADP-ribosylation(pADPr) modification in the DR5-associated DISC, which was associated with caspase 8 activation in the DISC. Our studies determined a novel function of PARP-1, independent of its known function in DNA repair, in regulating caspase 8 activation in the DISC. These results not only provide novel molecular insights into the function of PARP-1 in regulating the extrinsic apoptosis machinery, but also support the intervention of combining PARP inhibitors with death receptor agonists to enhance the efficacy of pancreatic cancer therapy.

Citation Format: Kaiyu Yuan, Yong Sun, Tong Zhou, Jay McDonald, Yabing Chen. PARP-1 regulates death receptor 5-mediated apoptosis in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2947. doi:10.1158/1538-7445.AM2013-2947

©2013 American Association for Cancer Research
2013