Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells
Identifieur interne : 000520 ( Ncbi/Merge ); précédent : 000519; suivant : 000521Metabolic 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
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controls mutant p53 R248Q stability in acute myeloid leukemia cells</title><author><name sortKey="Allende Vega, Nerea" sort="Allende Vega, Nerea" uniqKey="Allende Vega N" first="Nerea" last="Allende-Vega">Nerea Allende-Vega</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9961 060X</institution-id><institution-id institution-id-type="GRID">grid.157868.5</institution-id><institution>IRMB, Univ Montpellier, INSERM, CHU Montpellier,</institution></institution-wrap>Montpellier, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Montpellier</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id 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><author><name sortKey="Villalba, Martin" sort="Villalba, Martin" uniqKey="Villalba M" first="Martin" last="Villalba">Martin Villalba</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9961 060X</institution-id><institution-id institution-id-type="GRID">grid.157868.5</institution-id><institution>IRMB, Univ Montpellier, INSERM, CHU Montpellier,</institution></institution-wrap>Montpellier, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Montpellier</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id 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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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30948782</article-id><article-id pub-id-type="pmc">6449403</article-id><article-id pub-id-type="publisher-id">42220</article-id><article-id pub-id-type="doi">10.1038/s41598-019-42220-y</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Allende-Vega</surname><given-names>Nerea</given-names></name><address><email>nerea.allende-vega@inserm.fr</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4385-4888</contrib-id><name><surname>Villalba</surname><given-names>Martin</given-names></name><address><email>martin.villalba@inserm.fr</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9961 060X</institution-id><institution-id institution-id-type="GRID">grid.157868.5</institution-id><institution>IRMB, Univ Montpellier, INSERM, CHU Montpellier,</institution></institution-wrap>Montpellier, France</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.462469.b</institution-id><institution>IRMB, CHU Montpellier,</institution></institution-wrap>Montpellier, France</aff></contrib-group><pub-date pub-type="epub"><day>4</day><month>4</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>4</day><month>4</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>9</volume><elocation-id>5637</elocation-id><history><date date-type="received"><day>23</day><month>10</month><year>2018</year></date><date date-type="accepted"><day>26</day><month>3</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><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></abstract><funding-group><award-group><funding-source><institution>INCA PRT-K 2018-021</institution></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>France</li></country></list><tree><country 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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|texte= Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells
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