The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

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.

Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies

“…As recently reviewed by Liu and colleagues, wt-p53 may not only positively modulate ferroptosis, but it may also have an anti-ferroptotic role. Many processes are involved in this mechanism, including protein complexes and miRNA [ 120 , 121 ]. In summary, p53 has context-dependent activity and may play a dual role.…”

“…In particular, when p53 carries GOF missense mutations, it is able to bind NRF2, inducing the transcriptional inhibition of SLC7A11. Mut-p53 cells are therefore sensitized to ferroptosis and less resistant to oxidative-damage-inducing drugs [ 120 ]. This clears the way for the rational development of combinatorial therapeutic strategies for mut-p53 cancer cells.…”

Targeting GRK5 for Treating Chronic Degenerative Diseases

“…For instance, more efforts should be made to understand the specific effects of the interaction between GRK5 and p53. Indeed, p53 is involved in several biological and pathological processes and recently, it has been associated with the regulation of ferroptosis [130]. This iron-dependent new form of programmed cell death is driven by lipid peroxidation and is involved in cancer, tissue ischemia/reperfusion injury, and neurodegeneration [130,131].…”

“…Indeed, p53 is involved in several biological and pathological processes and recently, it has been associated with the regulation of ferroptosis [ 130 ]. This iron-dependent new form of programmed cell death is driven by lipid peroxidation and is involved in cancer, tissue ischemia/reperfusion injury, and neurodegeneration [ 130 , 131 ]. Whether and how GRK5 via p53 regulates ferroptosis is an urgent question that deserves an immediate response.…”

The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer

“…A myriad of protein-coding genes and many non-coding genes, including microRNAs (miRNAs) and long non-coding RNAs (LncRNAs), have been identified as p53 target genes ( Feng and Levine, 2010 ; Liu et al, 2017a ; Dangelmaier et al, 2019 ; Levine, 2019 ). Through selective transcriptional induction or repression of these target genes, p53 regulates various cellular responses, including cell cycle arrest, senescence, apoptosis, autophagy, ferroptosis, DNA repair, metabolism, cell migration/invasion, modulation of oxidative stress, etc., which contribute to the role of p53 in tumor suppression ( Vousden and Prives, 2009 ; Muller and Vousden, 2014 ; Levine, 2019 ; Liu J. et al, 2019 ; Liu et al, 2020 ; Zhang et al, 2020 ). Besides of the role of p53 in tumor suppression, p53 has also been shown to play important roles in many other biological and pathological processes, such as anti-infection, immune response, maternal reproduction, development, metabolic diseases, ischemia and tissue injuries, neurodegeneration, and aging ( Hu, 2009 ; Levine and Oren, 2009 ; Vousden and Prives, 2009 ; Muller and Vousden, 2014 ; Levine, 2019 ; Liu J. et al, 2019 ; Zhang et al, 2020 ).…”