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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalMolecular Oncology
DOIs
Publication statusAccepted/In press - Dec 1 2015

Keywords

  • AMPK
  • Autophagy
  • Cancer
  • Gain-of-function
  • MTOR
  • Mutant p53

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

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  • Cite this

    Cordani, M., Oppici, E., Dando, I., Butturini, E., Dalla Pozza, E., Nadal-Serrano, M., Oliver, J., Roca, P., Mariotto, S., Cellini, B., Blandino, G., Palmieri, M., Di Agostino, S., & Donadelli, M. (Accepted/In press). Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition. Molecular Oncology. https://doi.org/10.1016/j.molonc.2016.04.001