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PARI overexpression promotes genomic instability and pancreatic tumorigenesis
- Source :
- Cancer research. 73(8)
- Publication Year :
- 2013
-
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. Cancer Res; 73(8); 2529–39. ©2013 AACR.
- Subjects :
- Genome instability
DNA Replication
Cancer Research
DNA Repair
DNA repair
DNA damage
Gene Expression
Biology
medicine.disease_cause
Genomic Instability
Article
S Phase
Mice
Pancreatic cancer
Cell Line, Tumor
medicine
Animals
Humans
Homologous Recombination
Cell Proliferation
Cell growth
medicine.disease
Molecular biology
Xenograft Model Antitumor Assays
Homologous Recombination Pathway
Tumor Burden
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
Cell Transformation, Neoplastic
Oncology
Cancer research
Homologous recombination
Carcinogenesis
Carrier Proteins
DNA Damage
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 73
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....b78fdc70e94987eb1dd264efae7da462