Oncotarget

Research Papers:

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

Melanie Schwermer _, Sangkyun Lee, Johannes Köster, Tom van Maerken, Harald Stephan, Angelika Eggert, Katharina Morik, Johannes H. Schulte and Alexander Schramm

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Oncotarget. 2015; 6:15425-15435. https://doi.org/10.18632/oncotarget.3908

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Abstract

Melanie Schwermer1, Sangkyun Lee2, Johannes Köster3, Tom van Maerken4, Harald Stephan1, Angelika Eggert5, Katharina Morik2, Johannes H. Schulte1,6,7,8,9, Alexander Schramm1

1Department of Pediatric Oncology and Hematology, University Children’s Hospital Essen, Essen, Germany

2Department of Computer Sciences, TU Dortmund University, Dortmund, Germany

3Department of Genome Informatics, University Hospital Essen, Essen, Germany

4Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium

5Charite University Medicine, Berlin, Germany

6Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany

7Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

8German Cancer Consortium (DKTK), Heidelberg, Germany

9German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Alexander Schramm, e-mail: [email protected]

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.


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