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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.

SUBMITTER: Schwermer M

PROVIDER: S-EPMC4558161 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Schwermer Melanie M Lee Sangkyun S Köster Johannes J van Maerken Tom T Stephan Harald H Eggert Angelika A Morik Katharina K Schulte Johannes H JH Schramm Alexander A

Oncotarget 20150601 17

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 s ...[more]

PMID: 26029996

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

Publications

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

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