Inhibition of WIP1 phosphatase sensitizes breast cancer cells to genotoxic stress and to MDM2 antagonist nutlin-3
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F16%3A00457376" target="_blank" >RIV/68378050:_____/16:00457376 - isvavai.cz</a>
Result on the web
<a href="http://dx.doi.org/10.18632/oncotarget.7363" target="_blank" >http://dx.doi.org/10.18632/oncotarget.7363</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.18632/oncotarget.7363" target="_blank" >10.18632/oncotarget.7363</a>
Alternative languages
Result language
angličtina
Original language name
Inhibition of WIP1 phosphatase sensitizes breast cancer cells to genotoxic stress and to MDM2 antagonist nutlin-3
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>x</sub> - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)
CEP classification
EB - Genetics and molecular biology
OECD FORD branch
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Result continuities
Project
<a href="/en/project/GAP305%2F12%2F2485" target="_blank" >GAP305/12/2485: Structure and function of proteins involved in DNA damage signaling</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2016
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
OncoTarget
ISSN
1949-2553
e-ISSN
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Volume of the periodical
7
Issue of the periodical within the volume
12
Country of publishing house
US - UNITED STATES
Number of pages
18
Pages from-to
14458-14475
UT code for WoS article
000375687200089
EID of the result in the Scopus database
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