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Pharmacological inhibition of WIP1 sensitizes acute myeloid leukemia cells to MDM2 inhibitor Nutlin-3a

ABSTRACT: Pharmacological inhibition of WIP1 sensitizes acute myeloid leukemia cells to MDM2 inhibitor Nutlin-3a

PROVIDER: PRJNA657008 | ENA |

REPOSITORIES: ENA

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Pharmacological inhibition of WIP1 sensitizes acute myeloid leukemia cells to MDM2 inhibitor Nutlin-3a

Project description:The wild-type p53-inducible protein phosphatase WIP1, encoded by the PPM1D gene, is a negative regulator of p53 and is involved in cell cycle control and DNA damage stress-response. In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in a number of combination strategies. We investigated the therapeutic potential of its inhibition through the selective WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in a panel of AML cell lines and performed gene expression analysis of single agent and combined treatments. A p53-related signature was significantly upregulated in the TP53-wildtype MV-4-11 AML cell line. Moreover, drug-specific transcriptional changes likely contribute to the synergistic combination effect.

2021-05-06 | GSE156182 | GEO

Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity

Project description:Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.

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Transcriptome-profiling (RNA-seq) and Ribosome-profiling (Ribo-seq) of BJ cells treated with Nutlin-3a, an MDM2 inhibitor, which induces p53.

Project description:We applied in parallel RNA-Seq and Ribosome-profiling analyses to immortalized human primary BJ fibroblast cells in which p53 was induced by Nutlin-3a RNA-seq, using Illumina HiSeq 2000, was applied to BJ cells treated with Nutlin-3a, at 5 timepoints: 0, 2, 4, 6, 19 hrs Ribosome profiling was applied to BJ cells treated with Nutlin-3a, at 5 timepoints: 0, 2, 4, 6, 19 hrs

2013-06-01 | E-GEOD-45785 | biostudies-arrayexpress

Expression data from human sarcoma patient samples treated with either vehicle control or Nutlin-3a

Project description:This study has examined the molecular mechanisms underlying sensitivity of sarcomas to Nutlin-3a, a non-genotoxic activator of the p53 pathway. Human patient material was collected immediately following surgical resection, dissected into small pieces and ex planted onto gelatin sponges immersed in media containing either vehicle control or Nutlin-3a (10uM and/or 50uM) for 48 hours. Nutlin-3a represents a novel targeted therapy for the treatment of sarcomas. We have examined expression profiles of genes upregulated in sarcoma patient derived tissues following nutlin-3a treatment ex vivo 16 samples ((Vehicle control and Nutlin-3a (10uM and 50uM) treated samples)) from 6 sarcoma patients

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Expression data from human sarcoma patient samples treated with either vehicle control or Nutlin-3a

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Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a.

Project description:In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from PPM1D, is a negative regulator of p53. We evaluated PPM1D expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples. PPM1D transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in NPM1-mutated (mut, irrespective of FLT3-ITD status) or TP53-mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of TP53-wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of TP53-mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in TP53-wt AML cell line and primary cells, but not in TP53-mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated TP53-wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11 TP53-wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in TP53-wt AML.

| S-EPMC8067413 | biostudies-literature

Interruption of p53-MDM2 Interaction by Nutlin-3a in Human Lymphoma Cell Models Initiates a Cell-Dependent Global Effect on Transcriptome and Proteome Level

Project description:In most lymphomas, p53 signaling pathway is inactivated by various mechanisms independent to p53 gene mutations or deletions. In many cases, p53 function is largely regulated by alterations in the protein abundance levels by the action of E3 ubiquitin-protein ligase MDM2, targeting p53 to proteasome-mediated degradation. In the present study, an integrating transcriptomics and pro-teomics analysis was employed to investigate the effect of p53 activation by a small-molecule MDM2-antagonist, nutlin 3a, on three lymphoma cell models following p53 activation. Our analy-sis revealed a system-wide nutlin 3a-associated effect in all examined lymphoma types, identifying in total of 4037 differentially affected proteins involved in a plethora of pathways, with significant heterogeneity among lymphomas. Our findings include known p53-targets and novel p53 activa-tion effects, involving transcription, translation, or degradation of protein components of path-ways, such as a decrease in key members of PI3K/mTOR pathway, heat-shock response, and gly-colysis, and an increase in key members of oxidative phoshosphorylation, autophagy and mito-chondrial translation. Combined inhibition of HSP90 or PI3K/mTOR pathway with nutlin 3a-mediated p53-activation enhanced the apoptotic effects suggesting a promising strategy against human lymphomas. Integrated omic profiling after p53 activation offered novel insights on the regulatory role specific proteins and pathways may have in lymphomagenesis.

2023-07-30 | PXD009290 | Pride

Transcriptome-profiling (RNA-seq) and Ribosome-profiling (Ribo-seq) of BJ cells treated with Nutlin-3a, an MDM2 inhibitor, which induces p53.

Project description:We applied in parallel RNA-Seq and Ribosome-profiling analyses to immortalized human primary BJ fibroblast cells in which p53 was induced by Nutlin-3a

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Transcriptomics analysis in 3T3L1 preadipocytes with activation of p53 via Nutlin-3a treatment

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