Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition.
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.
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Marco
M
Cordani
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Elisa
E
Oppici
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Ilaria
I
Dando
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Elena
E
Butturini
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Elisa
E
Dalla Pozza
Multidisciplinar Group of Translational Oncology, University Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, E07122 Palma de Mallorca, Balearic Islands, Spain; Physiopathology of Obesity and Nutrition, CIBERobn (CB06/03), Carlos III Health Research Institute, Spain.
Mercedes
M
Nadal-Serrano
Multidisciplinar Group of Translational Oncology, University Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, E07122 Palma de Mallorca, Balearic Islands, Spain; Physiopathology of Obesity and Nutrition, CIBERobn (CB06/03), Carlos III Health Research Institute, Spain.
Jordi
J
Oliver
Multidisciplinar Group of Translational Oncology, University Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, E07122 Palma de Mallorca, Balearic Islands, Spain; Physiopathology of Obesity and Nutrition, CIBERobn (CB06/03), Carlos III Health Research Institute, Spain.
Pilar
P
Roca
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Sofia
S
Mariotto
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Barbara
B
Cellini
Translational Oncogenomic Unit, Regina Elena National Cancer Institute-IFO, Rome, Italy.
Giovanni
G
Blandino
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
Marta
M
Palmieri
Translational Oncogenomic Unit, Regina Elena National Cancer Institute-IFO, Rome, Italy. Electronic address: diagostino@ifo.it.
Silvia
S
Di Agostino
Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. Electronic address: massimo.donadelli@univr.it.
Massimo
M
Donadelli
D000263:Adenylate Kinase / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D000071192:Autophagy-Related Protein 12 / Q000378:metabolism; D001483:Base Sequence; D000071186:Beclin-1 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; C491997:BECN1 protein, human; D000071186:Beclin-1; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
AMPK; Autophagy; Cancer; Gain-of-function; Mutant p53; mTOR