Recent findings on the role of wild-type and mutant p53 in cancer development and therapy

Abstract

The p53 protein is a tumor suppressor encoded by the TP53 gene and consists of 393 amino acids with four main functional domains. This protein responds to various cellular stresses to regulate the expression of target genes, thereby causing DNA repair, cell cycle arrest, apoptosis, metabolic changes, and aging. Mutations in the TP53 gene and the functions of the wild-type p53 protein (wtp53) have been linked to various human cancers. Eight TP53 gene mutations are located in codons, constituting 28% of all p53 mutations. The p53 can be used as a biomarker for tumor progression and an excellent target for designing cancer treatment strategies. In wild-type p53-carrying cancers, abnormal signaling of the p53 pathway usually occurs due to other unusual settings, such as high MDM2 expression. These differences between cancer cell p53 and normal cells have made p53 one of the most important targets for cancer treatment. In this review, we have dealt with various issues, such as the relative contribution of wild-type p53 loss of function, including transactivation-dependent and transactivation-independent activities in oncogenic processes and their role in cancer development. We also discuss the role of p53 in the process of ferroptosis and its targeting in cancer treatment. Finally, we focus on p53-related drug delivery systems and investigate the challenges and solutions.

The regulatory effects of p53 on the typical and atypical ferroptosis in the pathogenesis of osteosarcoma: A systematic review

“…Different studies have shown that atypical ferroptosis is either increased or decreased in osteosarcoma. Six studies ( Bouchalova et al, 2014 ; Xie et al, 2016 ; Gnanapradeepan et al, 2018 ; Su et al, 2022 ; Babamohamadi et al, 2022 ) have reported that atypical ferroptosis is enhanced in osteosarcoma. Table 4 summarizes the regulatory mechanisms of p53 on atypical ferroptosis.…”

“…Comparing the outcomes reported in Table 4 and the pathway illustrated in Figure 7 , we could deduce two possibilities from the regulatory outcomes of p53: enhanced ferroptosis or inhibited ferroptosis ( de Azevedo et al, 2019 ). Several studies ( Bouchalova et al, 2014 ; Xie et al, 2016 ; Gnanapradeepan et al, 2018 ; Su et al, 2022 ; Babamohamadi et al, 2022 ) have indicated that upregulation of p53 enhances atypical ferroptosis in the course of osteosarcoma, whereas other studies ( Komori, 2016 ; Van Maerken et al, 2014 ; Pang et al, 2020 ; Saraf et al, 2018 ; Yang and Zhang, 2013 ; Leroy et al, 2017 ) have reported that inactivation of p53 downregulates atypical ferroptosis in osteosarcoma.…”

“…We found evidence opposing the outcomes of p53 inactivation in ferroptosis in the course of osteosarcoma. Several studies (Bouchalova et al, 2014;Xie et al, 2016;Gnanapradeepan et al, 2018; Frontiers in Genetics frontiersin.org Babamohamadi et al, 2022;Su et al, 2022) have contended that p53 plays a central role in up-regulating atypical ferroptosis in the course of osteosarcoma through increasing the production of ROS, lipid and iron-mediated cell death, and cell proliferation (Table 4) (Liu and Gu, 2022b). Upregulation of atypical ferroptosis unfolds through increased production of ROS, lipid peroxidation and enhanced cell proliferation.…”

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer

“…In the biallelic context, when VAF-adjusted is ~50%, the presence of a non-functional TP53 protein can affect the function of the wild-type TP53, contributing to tumor progression (e.g., variants present in the oligomerization domain). [94][95][96] As none of the cases presented a germline variant classified as likely oncogenic or oncogenic in TP53, it can be presumed that somatic alterations in TP53 could be drivers of tumorigenesis. This hypothesis is also corroborated by the high frequency of TP53 somatic variants in premalignant lesions of the epithelium of the ovarian or fallopian tube.…”

“…In this work, most of the somatic variants (28/36) categorized as non‐functional or likely non‐functional presented a VAF‐adjusted ≥50%, indicating a prevalence of tumoral cells with non‐functional TP53 . In the biallelic context, when VAF‐adjusted is ~50%, the presence of a non‐functional TP53 protein can affect the function of the wild‐type TP53 , contributing to tumor progression (e.g., variants present in the oligomerization domain) 94–96 . As none of the cases presented a germline variant classified as likely oncogenic or oncogenic in TP53 , it can be presumed that somatic alterations in TP53 could be drivers of tumorigenesis.…”