PMID- 23833311
OWN - NLM
STAT- MEDLINE
DCOM- 20140616
LR  - 20220409
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 19
IP  - 17
DP  - 2013 Sep 1
TI  - PARP-1 regulates resistance of pancreatic cancer to TRAIL therapy.
PG  - 4750-9
LID - 10.1158/1078-0432.CCR-13-0516 [doi]
AB  - 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.
CI  - (c)2013 AACR.
FAU - Yuan, Kaiyu
AU  - Yuan K
AD  - Department of Pathology, University of Alabama at Birmingham, and the Birmingham 
      Veterans Affairs Medical Center, Birmingham, Alabama 35294, USA.
FAU - Sun, Yong
AU  - Sun Y
FAU - Zhou, Tong
AU  - Zhou T
FAU - McDonald, Jay
AU  - McDonald J
FAU - Chen, Yabing
AU  - Chen Y
LA  - eng
GR  - I01 BX002296/BX/BLRD VA/United States
GR  - P50 CA101955/CA/NCI NIH HHS/United States
GR  - P50CA101955/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130705
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Tnfsf10 protein, mouse)
RN  - EC 2.4.2.30 (Parp1 protein, mouse)
RN  - EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*administration & dosage/immunology
MH  - Apoptosis/genetics
MH  - Carcinogenesis/immunology
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mice
MH  - Pancreatic Neoplasms/*drug therapy/immunology
MH  - Poly (ADP-Ribose) Polymerase-1
MH  - Poly(ADP-ribose) Polymerase Inhibitors
MH  - Poly(ADP-ribose) Polymerases/*genetics/immunology
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*immunology
MH  - TNF-Related Apoptosis-Inducing Ligand/genetics/immunology
MH  - Xenograft Model Antitumor Assays
PMC - PMC4050702
MID - NIHMS589437
EDAT- 2013/07/09 06:00
MHDA- 2014/06/17 06:00
PMCR- 2014/06/10
CRDT- 2013/07/09 06:00
PHST- 2013/07/09 06:00 [entrez]
PHST- 2013/07/09 06:00 [pubmed]
PHST- 2014/06/17 06:00 [medline]
PHST- 2014/06/10 00:00 [pmc-release]
AID - 1078-0432.CCR-13-0516 [pii]
AID - 10.1158/1078-0432.CCR-13-0516 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2013 Sep 1;19(17):4750-9. doi: 10.1158/1078-0432.CCR-13-0516. 
      Epub 2013 Jul 5.