ArticleCell cycle (Georgetown, Tex.)2013
CDK4 inhibition restores G(1)-S arrest in MYCN-amplified neuroblastoma cells in the context of doxorubicin-induced DNA damage.
Article in Cell cycle (Georgetown, Tex.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 63 citations in OpenAlex.
- Comparative Functional Effects of Abemaciclib and Arcyriaflavin A inInternational journal of molecular sciences · 2026Article
- Tumor suppressor network dysregulation in neuroblastoma: molecular mechanisms and precision therapeutic opportunities.Frontiers in cell and developmental biology · 2026Review
- COCA-seq: genome-wide mapping of O-GlcNAc-associated open chromatin.Acta biochimica et biophysica Sinica · 2025Article
- Review
- Joint metabolomics and transcriptomics analysis systematically reveal the impact of MYCN in neuroblastoma.Scientific reports · 2024Article
- Inhibition of PI3 kinase isoform p110α suppresses neuroblastoma growth and induces the reduction of Anaplastic Lymphoma Kinase.Cell & bioscience · 2022Article
- Article
- The cyclin dependent kinase inhibitor p21Frontiers in oncology · 2022Article
- From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma.Journal of personalized medicine · 2021Review
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- Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma.Cells · 2021Article
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- An overview of neuroblastoma cell lineage phenotypes andExperimental biology and medicine (Maywood, N.J.) · 2020Review
- CDK4/6 inhibitors in P16/HPV16-negative squamous cell carcinoma of the head and neck.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2020Review
- Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells.Scientific reports · 2020Article
- Apoptotic effects of norfloxacin on corneal endothelial cells.Naunyn-Schmiedeberg's archives of pharmacology · 2020Article
- Rapamycin enhanced the antitumor effects of doxorubicin in myelogenous leukemia K562 cells by downregulating the mTOR/p70S6K pathway.Oncology letters · 2019Article
- Clinically Relevant Biomarker Discovery in High-Risk Recurrent Neuroblastoma.Cancer informatics · 2019Article
- Knockdown of long non-coding RNA linc00511 suppresses proliferation and promotes apoptosis of bladder cancer cells via suppressing Wnt/β-catenin signaling pathway.Bioscience reports · 2018Article
- CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest.Journal of translational medicine · 2017Article
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10 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Relapse with drug-resistant disease is the main cause of death in MYCN-amplified neuroblastoma patients. MYCN-amplified neuroblastoma cells in vitro are characterized by a failure to arrest at the G(1)-S checkpoint after irradiation- or drug-induced DNA damage. We show that several MYCN-amplified cell lines harbor additional chromosomal aberrations targeting p53 and/or pRB pathway components, including CDK4/CCND1/MDM2 amplifications, p16INK4A/p14ARF deletions or TP53 mutations. Cells with these additional aberrations undergo significantly lower levels of cell death after doxorubicin treatment compared with MYCN-amplified cells, with no additional mutations in these pathways. In MYCN-amplified cells CDK4 expression is elevated, increasing the competition between CDK4 and CDK2 for binding p21. This results in insufficient p21 to inhibit CDK2, leading to high CDK4 and CDK2 kinase activity upon doxorubicin treatment. CDK4 inhibition by siRNAs, selective small compounds or p19(INK4D) overexpression partly restored G(1)-S arrest, delayed S-phase progression and reduced cell viability upon doxorubicin treatment. Our results suggest a specific function of p19(INK4D), but not p16(INK4A), in sensitizing MYCN-amplified cells with a functional p53 pathway to doxorubicin-induced cell death. In summary, the CDK4/cyclin D-pRB axis is altered in MYCN-amplified cells to evade a G(1)-S arrest after doxorubicin-induced DNA damage. Additional chromosomal aberrations affecting the p53-p21 and CDK4-pRB axes compound the effects of MYCN on the G(1) checkpoint and reduce sensitivity to cell death after doxorubicin treatment. CDK4 inhibition partly restores G(1)-S arrest and sensitizes cells to doxorubicin-mediated cell death in MYCN-amplified cells with an intact p53 pathway.
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