title: Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors.
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.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Schwermer
authors.affiliation: Department of Computer Sciences, TU Dortmund University, Dortmund, Germany.
authors.forename: Sangkyun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Genome Informatics, University Hospital Essen, Essen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Köster
authors.affiliation: Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: van Maerken
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Stephan
authors.affiliation: Charite University Medicine, Berlin, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.affiliation: Department of Computer Sciences, TU Dortmund University, Dortmund, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Morik
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.|Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany.|Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016203:CDC2 Protein Kinase; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D056744:Cyclin B1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D012208:Rhabdomyosarcoma / Q000473:pathology*; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C534699:CCNB1 protein, human; D056744:Cyclin B1; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011804:Quinolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C512984:RO 3306; C495901:TP53 protein, human; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D053181:Caspase 8; D053453:Caspase 9
keywords: cdk1/CCNB1 complex; cell cycle; cyclin-dependent kinases