PARP-1 Regulates Resistance of Pancreatic Cancer to TRAIL Therapy

摘要: Purpose: Activating extrinsic apoptotic pathways targeting death receptors (DR) using agonistic antibodies or TNF-related apoptosis-inducing ligand (TRAIL) is promising for cancer therapy. However, most pancreatic cancers are resistant to TRAIL The present studies aimed identify combination therapies that enhance the efficacy of therapy and investigate underlying mechanisms. Experimental Design: A xenograft model in nude mice was used determine tumorigenesis therapeutic TRA-8, a monoclonal antibody DR5. Pancreatic cells were characterize mechanisms PARP-1 regulation TRA-8–induced apoptosis vitro . Results: found highly expressed TRA-8–resistant PANC-1 Suit-2 cells, compared with TRA-8–sensitive BxPc-3 MiaPaca-2. Inhibition pharmacologic inhibitor sensitized Suit2 dose-dependent manner. Furthermore, siRNAs specifically knocking down markedly enhanced augmented TRA-8 on vivo knockdown increased activation caspase-8 death-induced signaling complex (DISC). Immunoprecipitation DR5 identified recruitment PARP-1–mediated protein poly-ADP-ribosylation (pADPr) modification DR5-associated DISC. Further characterization revealed pADPr inhibited activation, which may contribute its function regulating resistance. Conclusions: Our provide molecular insights into novel machinery also support interventions combining inhibitors DR agonists Clin Cancer Res; 19(17); 4750–9. ©2013 AACR