2-[(4-Hydroxybenzyl) Amino] Phenol (HBAP) Restores the Mutated p53 to the Level Similar to That of Wild-Type p53 Protein and Inhibits Breast Cancer Growth in vivo to by Inducing Tumor Cells Apoptosis

Chenxi Xu,Xiaobo Zhang,Jianjian Zhuang

doi:10.3389/fcell.2020.574799

Chenxi Xu, Xiaobo Zhang + Show 1 more

Open Access

https://doi.org/10.3389/fcell.2020.574799

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Abstract

P53 is a transcriptional factor that plays important roles in apoptosis and is mutated in more than 50% of tumor cells. However, the restoration of mutated p53 to the level similar to wild-type p53 by a natural compound has not been explored intensively. In this study, the 2-[(4-hydroxybenzyl) amino] phenol (HBAP) compound, obtained from deep-sea virus-challenged thermophile Geobacillus sp. E263, interacted specifically with the mutated p53 protein. HBAP was able to induce apoptosis of p53-mutated breast cancer cells, but not normal breast cells and p53-unmutated breast cancer cells. HBAP activated the mutant p53 transcriptional activity by restoring the function of mutant p53 to that of wild-type p53. Further analysis indicated that HBAP bound only to the DNA binding domain of mutant p53 and that the interaction was dependent on the HBAP hydroxyl groups. In vivo data demonstrated that HBAP was toxicity-free and could suppress tumor growth by inducing tumor cell apoptosis. Therefore our findings revealed that recovering mutated p53 function to that of wild-type p53 caused by HBAP triggered cancer cell apoptosis and that metabolites from deep-sea virus-challenged thermophiles could be a promising source of anti-tumor drugs.

Highlights

Tumor suppressor p53 protein has been known to play very important roles in preventing tumor progression (Kastan et al, 1991; Yang et al, 2017)
Human cancer patients (N = 19,262) from the International Agency for Research on Cancer (IARC) TP53 database indicate that most mutations of p53 are located in the DNA-binding domain (DBD) domain (Amelio et al, 2016)
As mutations in p53 occur in human cancers and are critical to tumorigenesis, the restoration of mutant p53 to the wild-type has been explored by several studies in recent years

Summary

Introduction

Tumor suppressor p53 protein has been known to play very important roles in preventing tumor progression (Kastan et al, 1991; Yang et al, 2017). P21 is a CDK (cyclin-dependent kinase) inhibitory protein transcriptionally regulated by p53, whose activation leads to the cell cycle arrest in the G1 phase (Li et al, 1994; Martin et al, 2016). PUMA (p53 upregulated modulator of apoptosis) is a protein transcriptionally activated by p53 that can bind to Bcl located in the mitochondria to induce cytochrome c release, resulting in apoptosis (Vousden, 2005; Zhang et al, 2016). The p53 protein consists of three domains, the N-terminal transactivation domain (NTD), the central DNA-binding domain (DBD), and the carboxyl-terminal oligomerization and regulatory domain (CTD) (Bieging et al, 2014). The p53 protein forms a tetramer through the CTD domain

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