ArticleThe Journal of biological chemistry2010
Persistent p21 expression after Nutlin-3a removal is associated with senescence-like arrest in 4N cells.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- What Is Apoptosis and Why Is It Inhibited by the Most Important Tumor Suppressor (p53)?International journal of molecular sciences · 2025Review
- Role of Annexin 7 (ANXA7) as a Tumor Suppressor and a Regulator of Drug Resistance in Thyroid Cancer.International journal of molecular sciences · 2024Article
- Cisplatin Induces Senescent Lung Cancer Cell-Mediated Stemness Induction via GRP78/Akt-Dependent Mechanism.Biomedicines · 2022Article
- Senescent cells limit p53 activity via multiple mechanisms to remain viable.Nature communications · 2022Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- Article
- Small molecule activators of the p53 response.Journal of molecular cell biology · 2019Review
- Nutlin-loaded magnetic solid lipid nanoparticles for targeted glioblastoma treatment.Nanomedicine (London, England) · 2019Article
- Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization.EBioMedicine · 2018Article
- Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells.Journal of virology · 2018Article
- The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis.Cancer biology & therapy · 2017Article
- Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome.International journal of molecular sciences · 2017Review
- Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells.Oncotarget · 2017Article
- c-Abl inhibits breast cancer tumorigenesis through reactivation of p53-mediated p21 expression.Oncotarget · 2016Article
- Article
- The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.PLoS computational biology · 2014Article
- Attenuation of replication stress-induced premature cellular senescence to assess anti-aging modalities.Current protocols in cytometry · 2014Article
- Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells.Breast cancer research : BCR · 2014Article
- Article
- Low-dose etoposide-treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: Does the response involve senescence? The possible role of vimentin.Cancer cell international · 2013Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nutlin-3a is a preclinical drug that stabilizes p53 by blocking the interaction between p53 and MDM2. In our previous study, Nutlin-3a promoted a tetraploid G(1) arrest in two p53 wild-type cell lines (HCT116 and U2OS), and both cell lines underwent endoreduplication after Nutlin-3a removal. Endoreduplication gave rise to stable tetraploid clones resistant to therapy-induced apoptosis. Prior knowledge of whether cells are susceptible to Nutlin-induced endoreduplication and therapy resistance could help direct Nutlin-3a-based therapies. In the present study, Nutlin-3a promoted a tetraploid G(1) arrest in multiple p53 wild-type cell lines. However, some cell lines underwent endoreduplication to relatively high extents after Nutlin-3a removal whereas other cell lines did not. The resistance to endoreduplication observed in some cell lines was associated with a prolonged 4N arrest after Nutlin-3a removal. Knockdown of either p53 or p21 immediately after Nutlin-3a removal could drive endoreduplication in otherwise resistant 4N cells. Finally, 4N-arrested cells retained persistent p21 expression; expressed senescence-associated beta-galactosidase; displayed an enlarged, flattened phenotype; and underwent a proliferation block that lasted at least 2 weeks after Nutlin-3a removal. These findings demonstrate that transient Nutlin-3a treatment can promote an apparently permanent proliferative block in 4N cells of certain cell lines associated with persistent p21 expression and resistance to endoreduplication.
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