title: PARI overexpression promotes genomic instability and pancreatic tumorigenesis.
abstract: Treatment options for patients with pancreatic ductal adenocarcinoma (PDAC) remain limited. Therapeutic targets of interest include mutated molecules that predispose to pancreatic cancer such as KRAS and TP53. Here, we show that an element of the homologous recombination pathway of DNA repair, the PARP-binding protein C12orf48/PARI (PARPBP), is overexpressed specifically in pancreatic cancer cells where it is an appealing candidate for targeted therapy. PARI upregulation in pancreatic cancer cells or avian DT40 cells conferred DNA repair deficiency and genomic instability. Significantly, PARI silencing compromised cancer cell proliferation in vitro, leading to cell-cycle alterations associated with S-phase delay, perturbed DNA replication, and activation of the DNA damage response pathway in the absence of DNA damage stimuli. Conversely, PARI overexpression produced tolerance to DNA damage by promoting replication of damaged DNA. In a mouse xenograft model of pancreatic cancer, PARI silencing was sufficient to reduce pancreatic tumor growth in vivo. Taken together, our findings offered a preclinical proof-of-concept for PARI as candidate therapeutic target to treat PDAC.
authors: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Kevin W
authors: KW
authors: O'Connor
authors: Donniphat
authors: D
authors: Dejsuphong
authors: Eunmi
authors: E
authors: Park
authors: Claudia M
authors: CM
authors: Nicolae
authors: Alec C
authors: AC
authors: Kimmelman
authors: Alan D
authors: AD
authors: D'Andrea
authors: George-Lucian
authors: GL
authors: Moldovan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016196:S Phase; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C556015:PARPBP protein, human