The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway.

Wenwei Hu,Cen Zhang,Juan Liu,Zhaohui Feng,Jianming Wang

doi:10.3390/ijms21218387

Abstract

Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries.

Highlights

Tumor suppressor p53 plays a key role in tumor suppression [1,2,3,4]. p53 function is disrupted in many human cancers through mutations of the p53 gene and other mechanisms, including amplification and/or overexpression of p53 negative regulators (e.g., MDM2 and MDM4), which is a prerequisite for the initiation and/or progression of many human cancers [1,2,3,4,5]
As a new form of programmed cell death, remarkable progress has been made on the research on ferroptosis since its discovery in 2012, our current understanding of the molecular mechanism of ferroptosis, the role of ferroptosis in biological and pathological processes, as well as its application in treatments of cancer and other diseases is still limited
Further studies are warranted to understand whether this context dependence is caused by cell and tissue specificity, stress signal specificity and/or ferroptosis inducer specificity and to identify the signaling pathways and molecular mechanisms contributing to this context dependence

Summary

Introduction

Tumor suppressor p53 plays a key role in tumor suppression [1,2,3,4]. p53 function is disrupted in many human cancers through mutations of the p53 gene and other mechanisms, including amplification and/or overexpression of p53 negative regulators (e.g., MDM2 and MDM4), which is a prerequisite for the initiation and/or progression of many human cancers [1,2,3,4,5]. P53 mainly exerts its tumor suppressive function through selective transcriptional regulation of many target genes to regulate various fundamental cellular responses, including apoptosis, cell cycle arrest, senescence, DNA repair and metabolism [1,2,3,4]. Numerous studies have shown that many missense mutp proteins, including the hotspot mutp, display GOF activities to promote cancer progression in the absence of wild-type p53 [5,6,7,8,12,13]. GOF mutp interacts with select proteins in addition to transcription factors to regulate their levels, activities and/or functions to promote tumorigenesis [5,6,7,8,12,13]

The Signaling Pathways in Ferroptosis

Wild-Type p53 Inhibits Ferroptosis

Ferroptosis Regulated by MDM2 and MDM4 Independently of p53

Findings

Summary and Perspectives