RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification
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Paulina Ćwiek1, Zaira Leni1, Fabiana Salm1, Valeriya Dimitrova1, Beata Styp-Rekowska2, Gianpaolo Chiriano3, Michael Carroll4, Katrin Höland1, Valentin Djonov2, Leonardo Scapozza3, Patrick Guiry4 and Alexandre Arcaro1
1 Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland
2 Institute of Anatomy, University of Bern, Bern, Switzerland
3 Pharmaceutical Biochemistry, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
4 Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin, Ireland
Alexandre Arcaro, email:
Keywords: c-Myc, medulloblastoma, PCTK1, RNA interference, synthetic lethality
Received: August 19, 2014 Accepted: November 06, 2014 Published: November 06, 2014
Medulloblastoma (MB) is the most common malignant brain tumor in children and is associated with a poor outcome. cMYC amplification characterizes a subgroup of MB with very poor prognosis. However, there exist so far no targeted therapies for the subgroup of MB with cMYC amplification. Here we used kinome-wide RNA interference screening to identify novel kinases that may be targeted to inhibit the proliferation of c-Myc-overexpressing MB. The RNAi screen identified a set of 5 genes that could be targeted to selectively impair the proliferation of c-Myc-overexpressing MB cell lines: AKAP12 (A-kinase anchor protein), CSNK1α1 (casein kinase 1, alpha 1), EPHA7 (EPH receptor A7) and PCTK1 (PCTAIRE protein kinase 1). When using RNAi and a pharmacological inhibitor selective for PCTK1, we could show that this kinase plays a crucial role in the proliferation of MB cell lines and the activation of the mammalian target of rapamycin (mTOR) pathway. In addition, pharmacological PCTK1 inhibition reduced the expression levels of c-Myc. Finally, targeting PCTK1 selectively impaired the tumor growth of c-Myc-overexpressing MB cells in vivo. Together our data uncover a novel and crucial role for PCTK1 in the proliferation and survival of MB characterized by cMYC amplification.
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