Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells
Identifieur interne : 000044 ( France/Analysis ); précédent : 000043; suivant : 000045Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells
Auteurs : Nerea Allende-Vega [France] ; Martin Villalba [France]Source :
- Scientific Reports [ 2045-2322 ] ; 2019.
Abstract
Eliminating mutant p53 (mt p53) protein could be a useful strategy to treat mt p53 tumors and potentially improve the prognosis of cancer patients. In this study, we unveil different mechanisms that eliminate p53-R248Q, one of the most frequent mutants found in human cancers. We show that the Hsp90 inhibitor 17-AAG eliminates R248Q by stimulating macroautophagy under normal growth conditions. Metabolic stress induced by the pyruvate dehydrogenase kinase-1 (PDK1) inhibitor dichloroacetate (DCA) inhibits the macroautophagy pathway. This induces the accumulation of R248Q, which in addition further inhibits macroautophagy. Combination of DCA and 17-AAG further decreases the autophagy flux compared to DCA alone. Despite this, this co-treatment strongly decreases R248Q levels. In this situation of metabolic stress, 17-AAG induces the binding of p53-R248Q to Hsc70 and the activation of Chaperone-Mediated Autophagy (CMA), leading to higher R248Q degradation than in non-stress conditions. Thus, different metabolic contexts induce diverse autophagy mechanisms that degrade p53-R248Q, and under metabolic stress, its degradation is CMA-mediated. Hence, we present different strategies to eliminate this mutant and provide new evidence of the crosstalk between macroautophagy and CMA and their potential use to target mutant p53.
Url:
DOI: 10.1038/s41598-019-42220-y
PubMed: 30948782
PubMed Central: 6449403
Affiliations:
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institution-id-type="GRID">grid.462469.b</institution-id><institution>IRMB, CHU Montpellier,</institution></institution-wrap>Montpellier, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Montpellier</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Eliminating mutant p53 (mt p53) protein could be a useful strategy to treat mt p53 tumors and potentially improve the prognosis of cancer patients. In this study, we unveil different mechanisms that eliminate p53-R248Q, one of the most frequent mutants found in human cancers. We show that the Hsp90 inhibitor 17-AAG eliminates R248Q by stimulating macroautophagy under normal growth conditions. Metabolic stress induced by the pyruvate dehydrogenase kinase-1 (PDK1) inhibitor dichloroacetate (DCA) inhibits the macroautophagy pathway. This induces the accumulation of R248Q, which in addition further inhibits macroautophagy. Combination of DCA and 17-AAG further decreases the autophagy flux compared to DCA alone. Despite this, this co-treatment strongly decreases R248Q levels. In this situation of metabolic stress, 17-AAG induces the binding of p53-R248Q to Hsc70 and the activation of Chaperone-Mediated Autophagy (CMA), leading to higher R248Q degradation than in non-stress conditions. Thus, different metabolic contexts induce diverse autophagy mechanisms that degrade p53-R248Q, and under metabolic stress, its degradation is CMA-mediated. Hence, we present different strategies to eliminate this mutant and provide new evidence of the crosstalk between macroautophagy and CMA and their potential use to target mutant p53.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lane, Dp" uniqKey="Lane D">DP Lane</name></author><author><name sortKey="Crawford, Lv" uniqKey="Crawford L">LV Crawford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gudkov, Av" uniqKey="Gudkov A">AV Gudkov</name></author><author><name sortKey="Komarova, Ea" uniqKey="Komarova E">EA Komarova</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brosh, R" uniqKey="Brosh R">R Brosh</name></author><author><name sortKey="Rotter, V" uniqKey="Rotter V">V Rotter</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Cho, Y" uniqKey="Cho Y">Y Cho</name></author><author><name sortKey="Gorina, 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name="France"><noRegion><name sortKey="Allende Vega, Nerea" sort="Allende Vega, Nerea" uniqKey="Allende Vega N" first="Nerea" last="Allende-Vega">Nerea Allende-Vega</name></noRegion><name sortKey="Allende Vega, Nerea" sort="Allende Vega, Nerea" uniqKey="Allende Vega N" first="Nerea" last="Allende-Vega">Nerea Allende-Vega</name><name sortKey="Villalba, Martin" sort="Villalba, Martin" uniqKey="Villalba M" first="Martin" last="Villalba">Martin Villalba</name><name sortKey="Villalba, Martin" sort="Villalba, Martin" uniqKey="Villalba M" first="Martin" last="Villalba">Martin Villalba</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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