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Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells

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.
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Contributor : Martin Villalba Connect in order to contact the contributor
Submitted on : Friday, October 25, 2019 - 6:46:47 PM
Last modification on : Wednesday, November 3, 2021 - 6:11:53 AM
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Martin Villalba, Nerea Allende-Vega. Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells. Scientific Reports, Nature Publishing Group, 2019, 9 (1), pp.5637. ⟨10.1038/s41598-019-42220-y⟩. ⟨inserm-02334210⟩



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