Mutant p53 as a guardian of the cancer cell

Fiamma Mantovani,Licio Collavin,Giannino Del Sal

doi:10.1038/s41418-018-0246-9

Abstract

Forty years of research have established that the p53 tumor suppressor provides a major barrier to neoplastic transformation and tumor progression by its unique ability to act as an extremely sensitive collector of stress inputs, and to coordinate a complex framework of diverse effector pathways and processes that protect cellular homeostasis and genome stability. Missense mutations in the TP53 gene are extremely widespread in human cancers and give rise to mutant p53 proteins that lose tumor suppressive activities, and some of which exert trans-dominant repression over the wild-type counterpart. Cancer cells acquire selective advantages by retaining mutant forms of the protein, which radically subvert the nature of the p53 pathway by promoting invasion, metastasis and chemoresistance. In this review, we consider available evidence suggesting that mutant p53 proteins can favor cancer cell survival and tumor progression by acting as homeostatic factors that sense and protect cancer cells from transformation-related stress stimuli, including DNA lesions, oxidative and proteotoxic stress, metabolic inbalance, interaction with the tumor microenvironment, and the immune system. These activities of mutant p53 may explain cancer cell addiction to this particular oncogene, and their study may disclose tumor vulnerabilities and synthetic lethalities that could be exploited for hitting tumors bearing missense TP53 mutations.

Highlights

Tumors evolve through genetic and epigenetic changes that modify fundamental cellular programs of growth and proliferation, followed by selection of reprogrammed cells that best adapt to a variety of suboptimal or challenging conditions they encounter, either transiently or durably, during progression.The most frequently altered gene in human tumors is TP53 [1], encoding the p53 protein
We have recently demonstrated that RhoA activation and actindependent mechano-transduction induced by elevated extracellular matrix (ECM) stiffness promote activation of Hsp90 by the mechanosensitive HDAC6 deacetylase, leading to mutp53 stabilization [19, 20] (Fig. 2)
We found that stress-induced phosphorylation at Ser/Thr-Pro sites, with subsequent Pin1-dependent isomerization, enhances the ability of mutp53 to neutralize p63 anti-metastatic activity and to induce a gene expression program associated with breast cancer aggressiveness and poor prognosis [29]

Summary

Introduction

Proliferation, followed by selection of reprogrammed cells that best adapt to a variety of suboptimal or challenging conditions they encounter, either transiently or durably, during progression. While blocking DDR activation on one hand, on the other hand mutp stimulates PARP function as a stress support mechanism allowing tumor cell survival in face of high levels of DNA damage These activities likely underlie mutp53-dependent adaptive responses promoting chemotherapy and radiotherapy resistance in tumor cells. The ability of mutp to inhibit autophagy and promote cell survival by stimulating the mTOR pathway sensitized mutp53-expressing breast and pancreas cancer cells to treatment with the mTOR inhibitor Everolimus [58] Along this line, it has been recently shown that. While no specific Pin inhibitor has yet reached clinical trials, it has been discovered that All-trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO), used for treatment of acute promyelocytic leukemia, directly interact with the Pin active site, leading to inhibition and degradation of Pin in tumor cells, and to blockade of several Pin1-dependent cancer-driving pathways [95, 96]. Interaction of KPT-6566 with the Pin catalytic site releases a quinone-mimicking drug that generates reactive oxygen species, combining Pin1/mutp inhibition with oxidative stress overload in cancer cells

Concluding remarks

Compliance with ethical standards