Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors

// Melanie Schwermer 1 , Sangkyun Lee 2 , Johannes Köster 3 , Tom van Maerken 4 , Harald Stephan 1 , Angelika Eggert 5 , Katharina Morik 2 , Johannes H. Schulte 1, 6, 7, 8, 9 , Alexander Schramm 1 1 Department of Pediatric Oncology and Hematology, University Children’s Hospital Essen, Essen, Germany 2 Department of Computer Sciences, TU Dortmund University, Dortmund, Germany 3 Department of Genome Informatics, University Hospital Essen, Essen, Germany 4 Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium 5 Charite University Medicine, Berlin, Germany 6 Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany 7 Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany 8 German Cancer Consortium (DKTK), Heidelberg, Germany 9 German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence to: Alexander Schramm, e-mail: alexander.schramm@uni-due.de Keywords: cell cycle, cyclin-dependent kinases, cdk1/CCNB1 complex Received: January 06, 2015 Accepted: April 28, 2015 Published: May 11, 2015 ABSTRACT Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks.