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• W2912763301 abstract "High-risk neuroblastomas are characterized by a near-di/tetraploid DNA index, structural chromosomal alterations, including MYCN amplification, and therapy resistance especially after relapse, which is associated with poor outcome. Amplified MYCN is a powerful prognostic marker in neuroblastoma and contributes to nearly all aspects of tumor formation and progression. Firstly, mechanisms were defined how MYCN interferes with drug-induced DNA damage response in neuroblastoma. Flow cytometric cell cycle analyses of 14 neuroblastoma cell lines showed that cells with amplified MYCN and/or additional aberrations of p53 and/or pRB pathway members respond to doxorubicin treatment with an impaired G1-S arrest. In contrast, drug treatment resulted in G2/M cell enrichment and was associated with cell death resistance. CDK4, CDK2 and CDK1 activity remained high in MYCN-amplified cells after drug treatment. CDK4 and CDK2 competed for p21 binding, which resulted in high CDK4 activity and an insufficient amount of p21 to inhibit CDK2 activity. High CDK4 activity resulted in phosphorylation of pRB at Ser780 and increased SKP2 expression. Inhibition of CDK4, CDK2 or CDK1 using siRNA/shRNA methodology, small molecule compounds or induction of the CDK4 upstream regulator p19-INK4D, but not p16-INK4A, restored at least partly drug-induced G1-S arrest in MYCN-amplified cells. CDK4 or CDK1 inhibition further sensitized MYCN-amplified neuroblastoma cells for doxorubicin-induced cell death. Secondly, the role of MYCN in the origin of chromosomal instability in neuroblastoma was studied. High-risk neuroblastomas were characterized by high expression of MYCN/MYC and p53/pRB-E2F target genes significantly enriched in mitosis regulation, including MAD2L1. Tetraplodization and anaphase bridges associated with lagging chromosomes incorporated in micronuclei were observed in MYCN-amplified and TP53-mutated neuroblastoma cells or cell cultures stably expressing a p21CIP1 targeting shRNA. Potential aneuploidy specific lethal genes, including MAD2L1 and CDK1, were identified in MYCN-amplified and TP53-mutated neuroblastoma cells using a functional RNAi screening approach combined with live-cell imaging. Taken together, these results show that amplified MYCN deregulates important members of the cell cycle machinery to impair (i) the G1-S checkpoint and (ii) the metaphase-anaphase checkpoint to induce replication and mitotic stress, which together with aberrations of p53 and/or pRB pathway members results in an impaired drug-induced DNA damage response and polyploidy." @default.
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• W2912763301 date "2012-01-01" @default.
• W2912763301 modified "2023-09-24" @default.
• W2912763301 title "MYCN-dependent and -independent mechanisms targeting drug-induced DNA damage response and chromosomal instability in neuroblastoma cells" @default.
• W2912763301 hasPublicationYear "2012" @default.
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