PARP-1 regulates resistance of pancreatic cancer to TRAIL therapy.

Abstract

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 therapy. The present studies aimed to identify combination therapies that enhance the efficacy of TRAIL therapy and to investigate the underlying mechanisms.

EXPERIMENTAL DESIGN:

A xenograft model in nude mice was used to determine pancreatic cancer tumorigenesis and therapeutic efficacy of TRA-8, a monoclonal agonistic antibody for DR5. Pancreatic cancer cells were used to characterize mechanisms underlying PARP-1 regulation of TRA-8-induced apoptosis in vitro.

RESULTS:

PARP-1 was found highly expressed in the TRA-8-resistant PANC-1 and Suit-2 cells, compared with TRA-8-sensitive BxPc-3 and MiaPaca-2. Inhibition of PARP-1 with a pharmacologic inhibitor sensitized PANC-1 and Suit2 cells to TRA-8-induced apoptosis in a dose-dependent manner. Furthermore, siRNAs specifically knocking down PARP-1 markedly enhanced TRA-8-induced apoptosis in vitro and augmented the efficacy of TRA-8 therapy on tumorigenesis in vivo. PARP-1 knockdown increased TRA-8-induced activation of caspase-8 in the death-induced signaling complex (DISC). Immunoprecipitation with DR5 antibody identified the recruitment of PARP-1 and PARP-1-mediated protein poly-ADP-ribosylation (pADPr) modification in the DR5-associated DISC. Further characterization revealed that PARP-1-mediated pADPr modification of caspase-8 inhibited caspase-8 activation, which may contribute to its function in regulating TRA-8 resistance.

CONCLUSIONS:

Our studies provide molecular insights into a novel function of PARP-1 in regulating the extrinsic apoptosis machinery and also support interventions combining PARP-1 inhibitors with DR agonists for pancreatic cancer therapy.

• Authors: Kaiyu Yuan, Yong Sun, Tong Zhou, Jay McDonald, Yabing Chen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 17 Pg. 4750-9 (Sep 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23833311 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2013 AACR.

Chemical References

• Antibodies, Monoclonal
• Poly(ADP-ribose) Polymerase Inhibitors
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Tnfsf10 protein, mouse
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, immunology)
• Apoptosis (genetics)
• Carcinogenesis (immunology)
• Drug Resistance, Neoplasm (genetics)
• Gene Knockdown Techniques
• Humans
• Mice
• Pancreatic Neoplasms (drug therapy, immunology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (genetics, immunology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (immunology)
• TNF-Related Apoptosis-Inducing Ligand (genetics, immunology)
• Xenograft Model Antitumor Assays