Genetic Screening for Synthetic Lethal Partners of Polynucleotide Kinase/Phosphatase: Potential for Targeting SHP-1–Depleted Cancers
| Autor: | Jonathan Penner-Chea, Michael Weinfeld, Todd R. Mereniuk, Robert A. Maranchuk, Gary K. Freschauf, Anja Schindler, Samar A. Hegazy, Raymond Lai, Edan Foley |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Lung Neoplasms animal structures Polynucleotide Kinase DNA damage Phosphatase PTPN6 Breast Neoplasms chemical and pharmacologic phenomena Adenocarcinoma Biology Transfection chemistry.chemical_compound Cell Line Tumor DNA Repair Protein Humans Genetic Testing RNA Small Interfering Cell Death Protein Tyrosine Phosphatase Non-Receptor Type 6 hemic and immune systems Molecular biology Phosphotransferases (Alcohol Group Acceptor) DNA Repair Enzymes Oncology chemistry embryonic structures MCF-7 Cells Female biological phenomena cell phenomena and immunity DNA Genetic screen |
| Zdroj: | Cancer Research. 72:5934-5944 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-12-0939 |
| Popis: | A genetic screen using a library of 6,961 siRNAs led to the identification of SHP-1 (PTPN6), a tumor suppressor frequently mutated in malignant lymphomas, leukemias, and prostate cancer, as a potential synthetic lethal partner of the DNA repair protein polynucleotide kinase/phosphatase (PNKP). After confirming the partnership with SHP-1, we observed that codepletion of PNKP and SHP-1 induced apoptosis. A T-cell lymphoma cell line that is SHP-1 deficient (Karpas 299) was shown to be sensitive to a chemical inhibitor of PNKP, but resistance was restored by expression of wild-type SHP-1 in these cells. We determined that while SHP-1 depletion does not significantly impact DNA strand-break repair, it does amplify the level of reactive oxygen species (ROS) and elevate endogenous DNA damage. The ROS scavenger WR1065 afforded protection to SHP-1–depleted cells treated with the PNKP inhibitor. We propose that codisruption of SHP-1 and PNKP leads to an increase in DNA damage that escapes repair, resulting in the accumulation of cytotoxic double-strand breaks and induction of apoptosis. This supports an alternative paradigm for synthetic lethal partnerships that could be exploited therapeutically. Cancer Res; 72(22); 5934–44. ©2012 AACR. |
| Databáze: | OpenAIRE |
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