Synthetic lethal targeting of PTEN-deficient cancer cells using selective disruption of polynucleotide kinase/phosphatase.

Abstract

A recent screen of 6,961 siRNAs to discover possible synthetic lethal partners of the DNA repair protein polynucleotide kinase/phosphatase (PNKP) led to the identification of the potent tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Here, we have confirmed the PNKP/PTEN synthetic lethal partnership in a variety of different cell lines including the PC3 prostate cancer cell line, which is naturally deficient in PTEN. We provide evidence that codepletion of PTEN and PNKP induces apoptosis. In HCT116 colon cancer cells, the loss of PTEN is accompanied by an increased background level of DNA double-strand breaks, which accumulate in the presence of an inhibitor of PNKP DNA 3'-phosphatase activity. Complementation of PC3 cells with several well-characterized mutated PTEN cDNAs indicated that the critical function of PTEN required to prevent toxicity induced by an inhibitor of PNKP is most likely associated with its cytoplasmic lipid phosphatase activity. Finally, we show that modest inhibition of PNKP in a PTEN knockout background enhances cellular radiosensitivity, suggesting that such a "synthetic sickness" approach involving the combination of PNKP inhibition with radiotherapy may be applicable to PTEN-deficient tumors.

• Authors: Todd R Mereniuk, Mohamed A M El Gendy, Ana M Mendes-Pereira, Christopher J Lord, Sunita Ghosh, Edan Foley, Alan Ashworth, Michael Weinfeld
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 10 Pg. 2135-44 (Oct 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23883586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• RNA, Small Interfering
• PNKP protein, human
• Phosphotransferases (Alcohol Group Acceptor)
• PTEN Phosphohydrolase
• PTEN protein, human
• DNA Repair Enzymes

Topics

• Apoptosis (genetics)
• Cell Line, Tumor
• DNA Breaks, Double-Stranded
• DNA Repair (genetics)
• DNA Repair Enzymes (antagonists & inhibitors, genetics)
• Gene Knockout Techniques
• HCT116 Cells
• Humans
• Molecular Targeted Therapy
• Neoplasms (drug therapy, genetics, pathology, radiotherapy)
• PTEN Phosphohydrolase (genetics)
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, genetics)
• RNA, Small Interfering
• Radiation Tolerance (drug effects)