Cytoplasmic PARP‐1 promotes pancreatic cancer tumorigenesis and resistance

• Published in: International journal of cancer Vol. 145; no. 2; pp. 474 - 483
• Main Authors: Xu, Fei, Sun, Yong, Yang, Shan‐Zhong, Zhou, Tong, Jhala, Nirag, McDonald, Jay, Chen, Yabing
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15.07.2019; Wiley Subscription Services, Inc
• Subjects: Activation; Adenosine diphosphate; Animals; Antagonists; Antibodies, Monoclonal - pharmacology; Apoptosis; Cancer; Cell death; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytoplasm - metabolism; cytoplasmic PARP‐1; death receptor; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm - drug effects; Enzymatic activity; Gene Expression Regulation, Neoplastic; Humans; Maintenance; Male; Medical research; Mice; Mutagenesis; Mutagenesis, Site-Directed; Mutants; Neoplasm Grading; Neoplasm Transplantation; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phenanthrenes - pharmacology; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Ribose; Signal Transduction - drug effects; survival; Tumorigenesis; Up-Regulation - drug effects; Xenografts; cytoplasmic PARP-1; apoptosis; pancreatic cancer; survival; death receptor
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32108

The poly(ADP‐ribose) polymerases (PARP) play important roles in repairing damaged DNA during intrinsic cell death. We recently linked PARP‐1 to death receptor (DR)‐activated extrinsic apoptosis, the present studies sought to elucidate the function of cytoplasmic PARP‐1 in pancreatic cancer tumorigenesis and therapy. Using human normal and pancreatic cancer tissues, we analyzed the prevalence of cytoplasmic PARP‐1 expression. In normal human pancreatic tissues, PARP‐1 expression was present in the nucleus; however, cytoplasmic PARP‐1 expression was identified in pancreatic cancers. Therefore, cytoplasmic PARP‐1 mutants were generated by site‐direct mutagenesis, to determine a causative effect of cytoplasmic PARP‐1 on pancreatic cancer tumorigenesis and sensitivity to therapy with TRA‐8, a humanized DR5 antibody. PARP‐1 cytoplasmic mutants rendered TRA‐8 sensitive pancreatic cancer cells, BxPc‐3 and MiaPaCa‐2, more resistant to TRA‐8‐induced apoptosis; whereas wild‐type PARP‐1, localizing mainly in the nucleus, had no effects. Additionally, cytoplasmic PARP‐1, but not wild‐type PARP‐1, increased resistance of BxPc‐3 cells to TRA‐8 therapy in a mouse xenograft model in vivo. Inhibition of PARP enzymatic activity attenuated cytoplasmic PARP‐1‐mediated TRA‐8 resistance. Furthermore, increased cytoplasmic PARP‐1, but not wild‐type PARP‐1, was recruited into the TRA‐8‐activated death‐inducing signaling complex and associated with increased and sustained activation of Src‐mediated survival signals. In contrast, PARP‐1 knockdown inhibited Src activation. Taken together, we have identified a novel function and mechanism underlying cytoplasmic PARP‐1, distinct from nuclear PARP‐1, in regulating DR5‐activated apoptosis. Our studies support an innovative application of available PARP inhibitors or new cytoplasmic PARP‐1 antagonists to enhance TRAIL therapy for TRAIL‐resistant pancreatic cancers. What's new? Poly(ADP‐ribose) polymerases (PARP) play important roles in repairing damaged DNA during intrinsic cell death. Recently, PARP‐1 was also linked to death receptor (DR)‐activated extrinsic apoptosis. This study uncovers a new role of cytoplasmic expression of PARP‐1 in regulating DR5‐activated apoptosis in pancreatic cancer cells in vitro as well as regulating the sensitivity of pancreatic tumors to TRA‐8 therapy in vivo. The findings highlight cytoplasmic PARP‐1 as a potential new marker for pancreatic cancer progression and support an innovative application of currently available PARP inhibitors or the design of new inhibitors targeting cytoplasmic PARP‐1 to enhance the efficacy of DR targeted therapy.