Treatment with B-AP15 to Inhibit UCHL5 and USP14 Deubiquitinating Activity and Enhance P27 and Cyclin E1 for Tumors with Deficiency

Overview

Journal Technol Cancer Res Treat

Specialties Biomedical Engineering
Oncology
Pharmacology

Date 2022 Aug 16

PMID 35971329

Authors

Zong-Yuan Jiang

Jiang Hong

Ju-Hua Zhang

Xiao-Feng Wang

Yu-Shui Ma

Zhang-Xia Xiong

Hao-Ran Sun

Cong Cheng

Bang-Zhu Xie

Ji-Bin Liu

Yang-Gang Ouyang

Da Fu

Affiliations

Soon will be listed here.

Abstract

TP53 protein is lost or mutated in about half of all types of human cancers and small molecules to regulate mutant p53 repair, or interrupt ubiquitination degradation of p53 induced by E3-ubiquitin ligase Mdm2 have a potential application in clinical application. To inhibit the deubiquitinase activity of 19S proteasome and restore the p53 protein level, in this study, we utilized p53 knockout mice to test the anti-cancer effect of a specific USP14 and UCH37 inhibitor b-AP15. Our results show that UCHL5, USP14 and COPS5 are upregulated in p53-related tumors, and higher expression of these genes results in a shorter overall survival in patients with p53 deficiency. Treatment with b-AP15, a UCHL5 and USP14 deubiquitinating activity inhibitor in 19S regulatory subunit, induces tumor regression and prolong the survival period of tumor-loaded mice through down-regulation of COPS5 and its downstream AP-1 and E2F1, and up-regulation of the cell cycle-related proteins p27 and Cyclin E1. Thus, our results suggested that inhibition of UCHL5 and USP14 deubiquitinating activity in 19S proteasome may contribute an extensive approach to preventing tumor progress due to p53 deficiency.

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