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: Claudia Fiorini, Marta Menegazzi, Chiara Padroni, Ilaria Dando, Elisa Dalla Pozza, Alex Gregorelli, Chiara Costanzo, Marta Palmieri, Massimo Donadelli
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 18 Issue 3 Pg. 337-46 (Mar 2013) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 23238993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Furans
• NSC 652287
• Pyrimidines
• Tumor Suppressor Protein p53
• 3-methyladenine
• MTOR protein, human
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• CP 31398
• Adenine

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Adenine (analogs & derivatives, pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Enzyme Activation
• Furans (pharmacology)
• Humans
• Pancreatic Neoplasms (drug therapy)
• Pyrimidines (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)