TP53 mutations compromising p53 transcriptional function occur in more than 50 % of human cancers,including pancreatic adenocarcinoma, and render cancercells more resistant to conventional therapy. In the lastfew years, many efforts have been addressed to identifyp53-reactivating molecules able to restore the wild-typetranscriptionally competent conformation of the mutatedproteins. Here, we show that two of these compounds,CP-31398 and RITA, induce cell growth inhibition, apoptosis, and autophagy by activating p53/DNA binding andp53 phosphorylation (Ser15), without affecting the total p53amount. These effects occur in both wild-type and mutantp53 pancreatic adenocarcinoma cell lines, whereas they aremuch less pronounced in normal human primary fibroblasts.Furthermore, CP-31398 and RITA regulate the axis SESN1-2/AMPK/mTOR by inducing AMPK phosphorylation onThr172, which has a crucial role in the autophagic response.The protective role of autophagy in cell growth inhibition byCP-31398 and RITA is supported by the finding that theAMPK inhibitor compound C or the autophagy inhibitorschloroquine or 3-methyladenine sensitize both pancreaticadenocarcinoma cell lines to the apoptotic response inducedby p53-reactivating molecules. Our results demonstrate forthe first time a survival role for autophagy induced by p53-reactivating molecules, supporting the development of ananti-cancer therapy based on autophagy inhibition associated to p53 activation.

Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis.

Fiorini, Claudia;MENEGAZZI, Marta Vittoria;DANDO, Ilaria;DALLA POZZA, Elisa;Gregorelli, Alex;COSTANZO, Chiara;PALMIERI, Marta;DONADELLI, Massimo
2013

Abstract

TP53 mutations compromising p53 transcriptional function occur in more than 50 % of human cancers,including pancreatic adenocarcinoma, and render cancercells more resistant to conventional therapy. In the lastfew years, many efforts have been addressed to identifyp53-reactivating molecules able to restore the wild-typetranscriptionally competent conformation of the mutatedproteins. Here, we show that two of these compounds,CP-31398 and RITA, induce cell growth inhibition, apoptosis, and autophagy by activating p53/DNA binding andp53 phosphorylation (Ser15), without affecting the total p53amount. These effects occur in both wild-type and mutantp53 pancreatic adenocarcinoma cell lines, whereas they aremuch less pronounced in normal human primary fibroblasts.Furthermore, CP-31398 and RITA regulate the axis SESN1-2/AMPK/mTOR by inducing AMPK phosphorylation onThr172, which has a crucial role in the autophagic response.The protective role of autophagy in cell growth inhibition byCP-31398 and RITA is supported by the finding that theAMPK inhibitor compound C or the autophagy inhibitorschloroquine or 3-methyladenine sensitize both pancreaticadenocarcinoma cell lines to the apoptotic response inducedby p53-reactivating molecules. Our results demonstrate forthe first time a survival role for autophagy induced by p53-reactivating molecules, supporting the development of ananti-cancer therapy based on autophagy inhibition associated to p53 activation.
Autophagy; Pancreatic cancer; p53; AMPK; RITA
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/506550
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