RT Journal Article
T1 Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition
A1 Cordani, Marco
A1 Oppici, Elisa
A1 Dando, Ilaria
A1 Butturini, Elena
A1 Dalla Pozza, Elisa
A1 Nadal-Serrano, Mercedes
A1 Oliver, Jordi
A1 Roca, Pilar
A1 Mariotto, Sofia
A1 Cellini, Barbara
A1 Blandino, Giovanni
A1 Palmieri, Marta
A1 Di Agostino, Silvia
A1 Donadelli, Massimo
AB 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.
PB FEBS Press
SN 1878-0261
YR 2016
FD 2016
LK https://hdl.handle.net/20.500.14352/94638
UL https://hdl.handle.net/20.500.14352/94638
LA eng
NO Cordani, Marco, et al. «Mutant P53 Proteins Counteract Autophagic Mechanism Sensitizing Cancer Cells to mTOR Inhibition». Molecular Oncology, vol. 10, n.o 7, agosto de 2016, pp. 1008-29. https://doi.org/10.1016/j.molonc.2016.04.001.
NO This work was supported by Italian Association for Cancer Research (AIRC)-Fondazione CariPaRo, Padova, Italy (n. C98C13000210007); Joint Projects program 2015 from University of Verona to M. Donadelli (n. B12I15002320003); ItalianAssociation for Cancer Research (AIRC) to S. Di Agostino (AIRC IG-n.16984) and to G. Blandino (AIRC IG-n.14455). M. NadalSerrano was supported by a short-term fellowship for the stay abroad (University of Verona, Italy) from European Molecular Biology Organization (EMBO). I. Dando is a fellow of AIRC (AIRC-Fondazione CariPaRo, Padova, Italy) and NanoMedicine (Fondazione Cariverona, Project Verona Nanomedicine Initiative). E. Dalla Pozza is a fellow of ARC-Net (Applied Research on Cancer Network), University of Verona, Italy. E. Butturini is a fellow of Joint Project (University of Verona, Italy and Aboca, Sansepolcro, Arezzo, Italy).
NO Italian Association for Cancer Research
NO Fondazione CariPaRo (Italy)
NO University of Verona
NO Italian Association for Cancer Research
NO European Molecular Biology Organization
DS Docta Complutense
RD 9 abr 2025