Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition

Abstract

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.

Molecularly targeted therapies for p53-mutant cancers

“…Previous studies showed that genomic stress can induce autophagy in a p53-dependent fashion and wild-type p53 can activate autophagy by upregulating autophagy-related gene DRAM1 (damage-regulated autophagy modulator 1) (135). However, several line of recent studies demonstrated that specific p53 mutants (R175H, R273H, R273L) that localize in the cytoplasmic can gain new function to inhibit autophagy either through blockade of AMPK signaling or activation of Akt/mTOR signaling (136, 137). In contrast, other p53 mutants (P151H, R282W) that localize in the nucleus failed to inhibit autophagy (138).…”

“…In contrast, other p53 mutants (P151H, R282W) that localize in the nucleus failed to inhibit autophagy (138). Those cytoplasmic p53 mutants counteract the formation of autophagic vesicles and fusion with lysosomes through the repression of several key autophagy-related proteins and enzymes such as BECN1, DRAM1 and ATG12 (137). While AMPK activation triggers autophagy by inducing degradation of macromolecules, mTOR signaling inhibits autophagy by stimulating anabolic biosynthesis for cancer cell growth (139).…”

“…Consequently, the inhibition of autophagy by cytoplasmic p53 mutants increases the proliferation and survival of cancer cells. In addition, the Akt/mTOR activation by GOF p53 mutants sensitizes cancer cells to the treatment with mTOR inhibitor everolimus (137). Therefore, targeting inhibition of mTOR signaling to induce autophagy has potential therapeutic applications to treat human cancers harboring cytoplasmic p53 mutants.…”

Mutant p53 and mTOR/PKM2 regulation in cancer cells

“…Our research group recently published that mutant p53 stimulates mTOR signaling and that this event enhances the sensitivity of cancer cells bearing mutant TP53 gene to the mTOR inhibitor everolimus as compared with WTp53 counterpart . Mechanistically, mTOR signaling stimulation by mutant p53 might be mainly due by two events: (i) the blockage of the mTOR‐antagonist pathway of AMP‐activated protein kinase (AMPK) by mutant p53 ; (ii) the mutant p53‐mediated stimulation of growth factor receptors' signaling, as epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR), or transforming growth factor (TGF)‐β receptor, thus promoting PI3K/Akt pathway and in turn activating many downstream effectors including mTORC1 . In addition, Zhao et al .…”

Doxorubicin-Induced p53 Interferes with Mitophagy in Cardiac Fibroblasts

“…By inducing cell cycle arrest, p53 will prevent the tumor cell from proliferating or induce apoptosis. In other cases, gain-of-function mutant p53 forms can interfere with autophagy and promote anti-apoptotic pathways59 . In these instances, the mutant p53 actually promotes tumor proliferation.…”