Post-Translational Modifications of p53 in Ferroptosis: Novel Pharmacological Targets for Cancer Therapy

Abstract

The tumor suppressor p53 is a well-known cellular guardian of genomic integrity that blocks cell cycle progression or induces apoptosis upon exposure to cellular stresses. However, it is unclear how the remaining activities of p53 are regulated after the abrogation of these routine activities. Ferroptosis is a form of iron- and lipid-peroxide-mediated cell death; it is particularly important in p53-mediated carcinogenesis and corresponding cancer prevention. Post-translational modifications have clear impacts on the tumor suppressor function of p53. Here, we review the roles of post-translational modifications in p53-mediated ferroptosis, which promotes the elimination of tumor cells. A thorough understanding of the p53 functional network will be extremely useful in future strategies to identify pharmacological targets for cancer therapy.

Novel Insights on Ferroptosis Modulation as Potential Strategy for Cancer Treatment: When Nature Kills

“…Under normal conditions, p53 can increase tumor cell sensitivity to ferroptosis, promoting cell death. However, on exposure to stresses such as cysteine deprivation, p53 hinders ferroptosis (Friedmann Angeli et al, 2019 ; Zhang et al, 2022b ). To further elucidate the mechanism of p53 regulation, Wang et al ( 2016 ) conducted a screening to uncover previously unknown modifications of p53.…”

Antioxidant Systems as Modulators of Ferroptosis: Focus on Transcription Factors

“…However, given the extraordinary complexity and heterogeneity of this group of disorders, sensitivity to ferroptosis may vary greatly among different types of cancer cells. For example, p53, which exerts a critical role in inhibiting tumorigenesis and other cancer processes such as invasion, metastasis, and metabolism, has been reported to control ferroptosis-related genes to prevent tumor growth [ 63 , 64 ]. However, as discussed in detail in Section 4.6 it recently emerged that p53 has opposing effects on ferroptosis regulation in different tumor cells.…”

“…For example, suppressor of cytokine signaling 1 (SOCS1) mediates p53 phosphorylation at Ser15, leading to ferroptosis-related downregulation of SLC7A11 and upregulation of spermidine/spermine N1-acetyltransferase 1 (SAT1) [ 352 , 353 ], while the attenuation of p53 phosphorylation at Ser46 in hepatocellular carcinoma HepG2, mediated by zinc finger protein 498 (ZNF498), lowered ROS production and GSL2 expression, and raised GSH production, with a consequent increase of cell survival and p53-mediated ferroptosis inhibition [ 354 ]. Also, CBP acetylates p53 (at residue K98 in the mouse and residue K101 in the human) without affecting the p53 DNA-binding capacity or transcriptional activity and this PTM retained p53’s ability to repress SLC7A11 expression and induce ferroptosis Instead, acetylation of p53 at K320 activates CDKN1A/p21 expression, hindering ferroptosis [ 64 ].…”

Insight on Heterocycles as p53‐MDM2 Protein‐Protein Interaction Inhibitors: Molecular Mechanism for p53 Activation

“…This protein undergoes post‐translational modifications. Also, regulates the expression of different genes and physiological processes [5,6] . The tetramer of p53 binds with DNA to regulate gene expression, avoids mutations of the genome, and plays a crucial role in the apoptosis of cancer cells [7–9] .…”

“…Also, regulates the expression of different genes and physiological processes. [5,6] The tetramer of p53 binds with DNA to regulate gene expression, avoids mutations of the genome, and plays a crucial role in the apoptosis of cancer cells. [7][8][9] In contrast, a mouse double 2-minute homolog (MDM2), a negative regulator of p53, binds with this tumor protein and undergoes proteasomal degradation via ubiquitylation (Figure 1).…”