ArticleMolecular cancer2014
Molecular mechanisms of nutlin-3 involve acetylation of p53, histones and heat shock proteins in acute myeloid leukemia.
Article in Molecular cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 36 citations in OpenAlex.
- Pandora's Box of AML: HowBiomedicines · 2025Review
- Systematic Characterization of p53-Regulated Long Noncoding RNAs across Human Cancers Reveals Remarkable Heterogeneity among Different Tumor Types.Molecular cancer research : MCR · 2024Article
- Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment.Frontiers in pharmacology · 2024Review
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- Potential Anticancer Activity of Crude Ethanol, Ethyl Acetate, and Water Extracts ofBioMed research international · 2020Article
- The MDM2 ligand Nutlin-3 differentially alters expression of the immune blockade receptors PD-L1 and CD276.Cellular & molecular biology letters · 2020Article
- Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists.Cancers · 2019Review
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- Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death.Scientific reports · 2017Article
- Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia.BMC medical genomics · 2017Article
- Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2016Article
- The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells.Oncotarget · 2016Article
- Role of E3 ubiquitin ligases in gastric cancer.World journal of gastroenterology · 2015Review
- Therapeutic targeting the cell division cycle 25 (CDC25) phosphatases in human acute myeloid leukemia--the possibility to target several kinases through inhibition of the various CDC25 isoforms.Molecules (Basel, Switzerland) · 2014Review
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe small-molecule MDM2 antagonist nutlin-3 has proved to be an effective p53 activating therapeutic compound in several preclinical cancer models, including acute myeloid leukemia (AML). We and others have previously reported a vigorous acetylation of the p53 protein by nutlin-treatment. In this study we aimed to investigate the functional role of this p53 acetylation in nutlin-sensitivity, and further to explore if nutlin-induced protein acetylation in general could indicate novel targets for the enhancement of nutlin-based therapy.
resultsNutlin-3 was found to enhance the acetylation of p53 in the human AML cell line MOLM-13 (wild type TP53) and in TP53 null cells transfected with wild type p53 cDNA. Stable isotope labeling with amino acids in cell culture (SILAC) in combination with immunoprecipitation using an anti-acetyl-lysine antibody and mass spectrometry analysis identified increased levels of acetylated Histone H2B, Hsp27 and Hsp90 in MOLM-13 cells after nutlin-treatment, accompanied by downregulation of total levels of Hsp27 and Hsp90. Intracellular levels of heat shock proteins Hsp27, Hsp40, Hsp60, Hsp70 and Hsp90α were correlated to nutlin-sensitivity for primary AML cells (n = 40), and AML patient samples with low sensitivity to nutlin-3 tended to express higher levels of heat shock proteins than more responsive samples. Combination therapy of nutlin-3 and Hsp90 inhibitor geldanamycin demonstrated synergistic induction of apoptosis in AML cell lines and primary AML cells. Finally, TP53 null cells transfected with a p53 acetylation defective mutant demonstrated decreased heat shock protein acetylation and sensitivity to nutlin-3 compared to wild type p53 expressing cells.
conclusionsAltogether, our results demonstrate that nutlin-3 induces acetylation of p53, histones and heat shock proteins, and indicate that p53 acetylation status and the levels of heat shock proteins may participate in modulation of nutlin-3 sensitivity in AML.
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