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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Synthetic lethal targeting of PTEN-deficient cancer cells using selective disruption of polynucleotide kinase/phosphatase
Molecular Cancer Therapeutics, Volume 12, No. 10, Year 2013
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Description
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 thePC3prostate 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 ofDNAdoublestrand breaks, which accumulate in the presence of an inhibitor of PNKP DNA 3'-phosphatase activity. Complementation of PC3 cells with several well-characterized mutated PTENcDNAsindicated that the critical function ofPTEN required to prevent toxicity induced by an inhibitor ofPNKPis 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. © 2013 AACR.
Authors & Co-Authors
Mereniuk, Todd R.
Canada, Edmonton
University of Alberta
El Gendy, Mohamed A.M.
Canada, Edmonton
University of Alberta
Egypt, Giza
National Research Centre
Mendes-Pereira, Ana M.
United Kingdom, London
The Institute of Cancer Research
Lord, Christopher J.
United Kingdom, London
The Institute of Cancer Research
Ghosh, Sunita S.
Canada, Edmonton
University of Alberta
Foley, Edan
Canada, Edmonton
University of Alberta
Ashworth, Alan A.
United Kingdom, London
The Institute of Cancer Research
Weinfeld, Michael
Canada, Edmonton
University of Alberta
Statistics
Citations: 29
Authors: 8
Affiliations: 3
Identifiers
Doi:
10.1158/1535-7163.MCT-12-1093
ISSN:
15357163
e-ISSN:
15388514
Research Areas
Cancer
Genetics And Genomics