RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification.
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.
Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland.
Paulina
P
Ćwiek
Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland.
Zaira
Z
Leni
Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland.
Fabiana
F
Salm
Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland.
Valeriya
V
Dimitrova
Institute of Anatomy, University of Bern, Bern, Switzerland.
Beata
B
Styp-Rekowska
Pharmaceutical Biochemistry, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Gianpaolo
G
Chiriano
Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin, Ireland.
Michael
M
Carroll
Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland.
Katrin
K
Höland
Institute of Anatomy, University of Bern, Bern, Switzerland.
Valentin
V
Djonov
Pharmaceutical Biochemistry, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Leonardo
L
Scapozza
Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin, Ireland.
Patrick
P
Guiry
Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland.
Alexandre
A
Arcaro
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism*; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D018844:Cyclin-Dependent Kinases; C089463:PCTAIRE-1 protein kinase