Inhibition of WIP1 phosphatase sensitizes breast cancer cells to genotoxic stress and to MDM2 antagonist nutlin-3
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články
Grantová podpora
14-1176
Worldwide Cancer Research - United Kingdom
PubMed
26883108
PubMed Central
PMC4924728
DOI
10.18632/oncotarget.7363
PII: 7363
Knihovny.cz E-zdroje
- Klíčová slova
- WIP1 inhibitor, breast cancer, checkpoint, nutlin-3, p53,
- MeSH
- aminopyridiny farmakologie MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- chemorezistence * MeSH
- dipeptidy farmakologie MeSH
- imidazoly farmakologie MeSH
- lidé MeSH
- nádorové buňky kultivované MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory prsu farmakoterapie enzymologie patologie MeSH
- piperaziny farmakologie MeSH
- poškození DNA účinky léků MeSH
- proliferace buněk účinky léků MeSH
- proteinfosfatasa 2C antagonisté a inhibitory genetika metabolismus MeSH
- protoonkogenní proteiny c-mdm2 antagonisté a inhibitory genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminopyridiny MeSH
- dipeptidy MeSH
- GSK2830371 MeSH Prohlížeč
- imidazoly MeSH
- MDM2 protein, human MeSH Prohlížeč
- nádorový supresorový protein p53 MeSH
- nutlin 3 MeSH Prohlížeč
- piperaziny MeSH
- PPM1D protein, human MeSH Prohlížeč
- proteinfosfatasa 2C MeSH
- protoonkogenní proteiny c-mdm2 MeSH
- TP53 protein, human MeSH Prohlížeč
PP2C family serine/threonine phosphatase WIP1 acts as a negative regulator of the tumor suppressor p53 and is implicated in silencing of cellular responses to genotoxic stress. Chromosomal locus 17q23 carrying the PPM1D (coding for WIP1) is commonly amplified in breast carcinomas and WIP1 was proposed as potential pharmacological target. Here we employed a cellular model with knocked out PPM1D to validate the specificity and efficiency of GSK2830371, novel small molecule inhibitor of WIP1. We have found that GSK2830371 increased activation of the DNA damage response pathway to a comparable level as the loss of PPM1D. In addition, GSK2830371 did not affect proliferation of cells lacking PPM1D but significantly supressed proliferation of breast cancer cells with amplified PPM1D. Over time cells treated with GSK2830371 accumulated in G1 and G2 phases of the cell cycle in a p21-dependent manner and were prone to induction of senescence by a low dose of MDM2 antagonist nutlin-3. In addition, combined treatment with GSK2830371 and doxorubicin or nutlin-3 potentiated cell death through a strong induction of p53 pathway and activation of caspase 9. We conclude that efficient inhibition of WIP1 by GSK2830371 sensitizes breast cancer cells with amplified PPM1D and wild type p53 to chemotherapy.
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PPM1D activity promotes cellular transformation by preventing senescence and cell death
PPM1D activity promotes the replication stress caused by cyclin E1 overexpression
Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1
WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors
WIP1 phosphatase as pharmacological target in cancer therapy