British journal of cancer · 2013
An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.
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Linton A, Cheng Y Y, Griggs K, Schedlich Lyn, Kirschner M B, Gattani S, Srikaran S, Chuan-Hao Kao S, McCaughan B C, Klebe S, van Zandwijk N, Reid G
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
Предметные рубрики MeSH
ApoptosisBlood ProteinsCDC2 Protein KinaseCell CycleCell Cycle CheckpointsCell Cycle ProteinsCell Line, TumorCisplatinCytoskeletal ProteinsDNA RepairDNA ReplicationHumansLung NeoplasmsMesotheliomaMesothelioma, MalignantMolecular Targeted TherapyNuclear ProteinsPleural NeoplasmsPrognosisProtein Serine-Threonine KinasesProto-Oncogene ProteinsPurinesRNA InterferenceRetrospective StudiesRoscovitinePolo-Like Kinase 1