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Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition.
- Source :
-
Molecular oncology [Mol Oncol] 2016 Aug; Vol. 10 (7), pp. 1008-29. Date of Electronic Publication: 2016 Apr 12. - Publication Year :
- 2016
-
Abstract
- Mutations in TP53 gene play a pivotal role in tumorigenesis and cancer development. Here, we report that gain-of-function mutant p53 proteins inhibit the autophagic pathway favoring antiapoptotic effects as well as proliferation of pancreas and breast cancer cells. We found that mutant p53 significantly counteracts the formation of autophagic vesicles and their fusion with lysosomes throughout the repression of some key autophagy-related proteins and enzymes as BECN1 (and P-BECN1), DRAM1, ATG12, SESN1/2 and P-AMPK with the concomitant stimulation of mTOR signaling. As a paradigm of this mechanism, we show that atg12 gene repression was mediated by the recruitment of the p50 NF-κB/mutant p53 protein complex onto the atg12 promoter. Either mutant p53 or p50 NF-κB depletion downregulates atg12 gene expression. We further correlated the low expression levels of autophagic genes (atg12, becn1, sesn1, and dram1) with a reduced relapse free survival (RFS) and distant metastasis free survival (DMFS) of breast cancer patients carrying TP53 gene mutations conferring a prognostic value to this mutant p53-and autophagy-related signature. Interestingly, the mutant p53-driven mTOR stimulation sensitized cancer cells to the treatment with the mTOR inhibitor everolimus. All these results reveal a novel mechanism through which mutant p53 proteins promote cancer cell proliferation with the concomitant inhibition of autophagy.<br /> (Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Adenylate Kinase metabolism
Apoptosis drug effects
Autophagy-Related Protein 12 metabolism
Base Sequence
Beclin-1 metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Everolimus pharmacology
Gene Expression Regulation, Neoplastic drug effects
Humans
Models, Biological
Neoplasms genetics
Phosphorylation drug effects
Protein Binding drug effects
Signal Transduction drug effects
TOR Serine-Threonine Kinases metabolism
Transcription Factor RelA metabolism
Autophagy drug effects
Mutant Proteins metabolism
Neoplasms pathology
Protein Kinase Inhibitors pharmacology
TOR Serine-Threonine Kinases antagonists & inhibitors
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 10
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 27118659
- Full Text :
- https://doi.org/10.1016/j.molonc.2016.04.001