title: An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive tumour originating in the thoracic mesothelium. Prognosis remains poor with 9- to 12-month median survival, and new targets for treatments are desperately needed.
  
  
  
  Utilising an RNA interference (RNAi)-based screen of 40 genes overexpressed in tumours, including genes involved in the control of cell cycle, DNA replication and repair, we investigated potential therapeutic targets for MPM. Following in vitro characterisation of the effects of target silencing on MPM cells, candidates were assessed in tumour samples from 154 patients.
  
  
  
  Gene knockdown in MPM cell lines identified growth inhibition following knockdown of NDC80, CDK1 and PLK1. Target knockdown induced cell-cycle arrest and increased apoptosis. Using small-molecule inhibitors specific for these three proteins also led to growth inhibition of MPM cell lines, and Roscovitine (inhibitor of CDK1) sensitised cells to cisplatin. Protein expression was also measured in tumour samples, with markedly variable levels of CDK1 and PLK1 noted. PLK1 expression in over 10% of cells correlated significantly with a poor prognosis.
  
  
  
  These results suggest that RNAi-based screening has utility in identifying new targets for MPM, and that inhibition of NDC80, CDK1 and PLK1 may hold promise for treatment of this disease.
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: A
authors: A
authors: Linton
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: Y Y
authors: YY
authors: Cheng
authors: Department of Anatomical Pathology, Flinders Medical Centre, Bedford, SA, Australia.
authors: K
authors: K
authors: Griggs
authors: Lyn
authors: L
authors: Schedlich
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: M B
authors: MB
authors: Kirschner
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: S
authors: S
authors: Gattani
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: S
authors: S
authors: Srikaran
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: S
authors: S
authors: Chuan-Hao Kao
authors: Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital; The Baird Institute and Sydney Medical School, University of Sydney, Sydney, Australia.
authors: B C
authors: BC
authors: McCaughan
authors: Department of Anatomical Pathology, Flinders Medical Centre, Bedford, SA, Australia.
authors: S
authors: S
authors: Klebe
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: N
authors: N
authors: van Zandwijk
authors: Asbestos Diseases Research Institute (ADRI), University of Sydney, Concord, NSW 2139, Australia.
authors: G
authors: G
authors: Reid
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003598:Cytoskeletal Proteins; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000086002:Mesothelioma, Malignant; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D012189:Retrospective Studies; D000077546:Roscovitine; D000097869:Polo-Like Kinase 1
chemical_list: D001798:Blood Proteins; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D002945:Cisplatin; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011687:Purines; D000077546:Roscovitine; D000097869:Polo-Like Kinase 1; C120529:NDC80 protein, human; C053635:factor XIIa inhibitor