Journal Article

Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition

Cordani, Marco, Oliver, Jordi, Mariotto, Sofia, Donadelli, Massimo, Palmieri, Marta, Nadal-Serrano, Mercedes, Di Agostino, Silvia, Oppici, Elisa, Blandino, Giovanni, Dando, Ilaria, Dalla Pozza, Elisa, Roca, Pilar, Butturini, Elena, Cellini, Barbara

2016

Overview

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. •GOF p53 mutant proteins inhibit the autophagic vesicle formation in cancer cells.•Mutant p53 proteins inhibit the expression of ATGs in cancer cells and patients.•Mutant p53/NF-κB p50 complex inhibits atg12 gene expression.•Mutant p53 proteins stimulate mTOR and repress AMPK signaling.•The expression of mutant p53 proteins sensitizes cancer cells to mTOR inhibition.

• Publisher: Elsevier B.V,Wiley,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 3207 Patología / 616-006.04 / Adenylate Kinase / Adenylate Kinase - metabolism / AMPK / AMPK; autophagy; cancer; gain-of-function; mutant p53; mTOR / Apoptosis / Apoptosis - drug effects / Autophagy / Autophagy - drug effects / Autophagy-Related Protein 12 / Autophagy-Related Protein 12 - metabolism / Base Sequence / Beclin-1 / Beclin-1 - metabolism / Breast cancer / Cancer / Cancer therapies / Cell culture / Cell cycle / Cell growth / Cell Line, Tumor / Cell Proliferation / Cell Proliferation - drug effects / DNA damage / Everolimus / Everolimus - pharmacology / Gain-of-function / Gene expression / Gene Expression Regulation, Neoplastic / Gene Expression Regulation, Neoplastic - drug effects / Humans / Kinases / Lysosomes / Medical research / Metabolism / Metastases / Models, Biological / mTOR / Mutant p53 / Mutant Proteins / Mutant Proteins - metabolism / Mutation / Neoplasms / Neoplasms - genetics / Neoplasms - pathology / Neoplasms. Tumors. Oncology. Including cancer and carcinogens / Oncología / p53 Protein / Pancreas / Pancreatic cancer / Phagocytosis / Phosphorylation / Phosphorylation - drug effects / Protein Binding / Protein Binding - drug effects / Protein Kinase Inhibitors / Protein Kinase Inhibitors - pharmacology / Proteins / RC254-282 / Signal Transduction / Signal Transduction - drug effects / TOR protein / TOR Serine-Threonine Kinases / TOR Serine-Threonine Kinases - antagonists & inhibitors / TOR Serine-Threonine Kinases - metabolism / Transcription Factor RelA / Transcription Factor RelA - metabolism / Tumor Suppressor Protein p53 / Tumor Suppressor Protein p53 - metabolism / Tumorigenesis / Vesicle fusion