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.

Terpinen-4-ol Induces Autophagic and Apoptotic Cell Death in Human Leukemic HL-60 Cells

“…This could be induced by ROS generation and autophagosomal enzymes, such as cathepsin but further study is needed to elucidate this hypothesis. It has also been reported that Bcl-2 family proteins might interact with the autophagic proteins (ATGs) or Beclin-1 to turn on/off or switch the mode of cell deaths between apoptosis and autophagic cell death (Nishida et al, 2008;Kang et al, 2011;Fiorini et al, 2013;Naves et al, 2013). ATG5 also plays as a switch on autophagy to apoptosis (Yousefi et al, 2006) and JNK regulates dissociation of Bcl-2 and Beclin-1 (Wei et al, 2008).…”

Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine

“…These molecules have been reported to activate wt p53 response in mp53-carrying tumors and to induce apoptotic cell death [21][22][23][24][25]. Recently, we showed that p53-reactivating molecules could inhibit the proliferation of pancreatic adenocarcinoma cells bearing mp53 and that their effect was attenuated by an AMPK/p53-mediated cyto-protective autophagy [26]. In this study, we have characterized, at the molecular level, the induction of mp53 transcriptional GOF activity with the associated chemioresistance in PDAC cell lines treated with the standard chemotherapeutic drug GEM.…”

“…CP-31398 or RITA treatments have been reported to have a significant effect on apoptotic cell death and induction of autophagy in tumour cells [26,34]. To investigate the possible effects of GEM/CP-31398 combined treatment in apoptosis and autophagy, we analyzed the apoptotic response (annexinV-FITC binding) and the amount of autophagosome formation (monodansylcadaverine staining) in both Panc1 and PaCa3 cell lines treated with GEM and/or CP-31398 for 48 h. The combined GEM/CP-31398 treatment led to induction of both apoptosis and autophagy at much higher levels than that observed with the single treatments ( Fig.…”

The Responses of Autophagy and Apoptosis to Oxidative Stress in Nucleus Pulposus Cells: Implications for Disc Degeneration

“…Autophagy could either inhibit or delay the occurrence of apoptosis [20,21,22,23,24,25], or promote apoptosis [26,27]. One of the most important factors involved the control and regulation of apoptosis and autophagy is the cellular redox status [28], which is determined by the balance between the rates of production and breakdown of reactive oxygen species (ROS) [29].…”