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.
Complete list of metadatas

Cited literature [52 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02334210
Contributor : Martin Villalba <>
Submitted on : Friday, October 25, 2019 - 6:46:47 PM
Last modification on : Saturday, October 26, 2019 - 1:49:29 AM

File

247734_1_merged_1550852868.pdf
Files produced by the author(s)

Identifiers

Collections

Citation

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⟩

Share

Metrics

Record views

215

Files downloads

14