title: NLK is a novel therapeutic target for PTEN deficient tumour cells.
abstract: PTEN (Phosphatase and tensin homolog) is a tumour suppressor gene commonly defective in human cancer, and is thus a potentially important therapeutic target. Targeting tumour suppressor loss-of-function is possible by exploiting the genetic concept of synthetic lethality (SL). By combining the use of isogenic models of PTEN deficiency with high-throughput RNA interference (RNAi) screening, we have identified Nemo-Like Kinase (NLK) inhibition as being synthetically lethal with PTEN deficiency. This SL is likely mediated by the transcription factor FOXO1 (Forkhead box O1), an NLK substrate, as the selectivity of NLK gene silencing for PTEN deficient cells can be reversed by FOXO1 knockdown. In addition, we provide evidence that PTEN defective cells targeted by NLK gene depletion undergo senescence, suggesting that NLK function is critical for the continued proliferation of PTEN deficient cells. Taken together, these data provide new insight into the potential of targeting of NLK to treat a range of tumourigenic conditions characterised by PTEN deficiency.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Mendes-Pereira
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C491731:IKBKG protein, human; D008565:Membrane Proteins; D051550:I-kappa B Kinase; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase