title: Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis.
abstract: TP53 mutations compromising p53 transcriptional function occur in more than 50 % of human cancers, including pancreatic adenocarcinoma, and render cancer cells more resistant to conventional therapy. In the last few years, many efforts have been addressed to identify p53-reactivating molecules able to restore the wild-type transcriptionally competent conformation of the mutated proteins. Here, we show that two of these compounds, CP-31398 and RITA, induce cell growth inhibition, apoptosis, and autophagy by activating p53/DNA binding and p53 phosphorylation (Ser15), without affecting the total p53 amount. These effects occur in both wild-type and mutant p53 pancreatic adenocarcinoma cell lines, whereas they are much less pronounced in normal human primary fibroblasts. Furthermore, CP-31398 and RITA regulate the axis SESN1-2/AMPK/mTOR by inducing AMPK phosphorylation on Thr172, which has a crucial role in the autophagic response. The protective role of autophagy in cell growth inhibition by CP-31398 and RITA is supported by the finding that the AMPK inhibitor compound C or the autophagy inhibitors chloroquine or 3-methyladenine sensitize both pancreatic adenocarcinoma cell lines to the apoptotic response induced by p53-reactivating molecules. Our results demonstrate for the first time a survival role for autophagy induced by p53-reactivating molecules, supporting the development of an anti-cancer therapy based on autophagy inhibition associated to p53 activation.
authors.affiliation: Department of Life and Reproduction Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorini
authors.forename: Marta
authors.initials: M
authors.lastname: Menegazzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Padroni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dando
authors.forename: Elisa
authors.initials: E
authors.lastname: Dalla Pozza
authors.forename: Alex
authors.initials: A
authors.lastname: Gregorelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Costanzo
authors.forename: Marta
authors.initials: M
authors.lastname: Palmieri
authors.forename: Massimo
authors.initials: M
authors.lastname: Donadelli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005663:Furans / Q000494:pharmacology; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005663:Furans; C118989:NSC 652287; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C025946:3-methyladenine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C402665:CP 31398; D000225:Adenine