P53-derived hybrid peptides induce apoptosis of synovial fibroblasts in the rheumatoid joint.

Shih-Yao Chen,Chao-Liang Wu,Chrong-Reen Wang,Ai-Li Shiau

doi:10.18632/oncotarget.23268

Abstract

Loss of p53-mediated suppression by its dominant-negative counterpart is commonly observed in human cancers, and activating p73 is a therapeutic strategy in p53-mutated oncological patients. In synovial fibroblasts (SFs) from rheumatoid arthritis (RA), mutant p53 can lead to the transformation-like features with resistance to the apoptosis induction. We examined whether intra-articular (i.a.) administration of p53-derived hybrid peptides to activate p73 can induce apoptosis of SFs by using adenoviral vectors encoding 37 amino acid (Ad37AA), a p53-derived hybrid peptide capable of activating p73, to transduce SFs in vitro and inject collagen-induced arthritis (CIA) joints in vivo. Increased p73 expression was found in synovial lining layers and SFs of RA patients and CIA rats. Higher expression of p53 up-regulated modulator of apoptosis (PUMA) and Bax with enhanced apoptosis were found in Ad37AA-transduced SFs, and silencing p73 abrogated the up-regulation of PUMA and Bax. Articular indexes and histologic scores were reduced in Ad37AA-injected joints with decreased SF densities, increased apoptotic cell numbers, and higher PUMA expression levels. We demonstrate that i.a. administration of p53-derived hybrid peptides can activate p73 to induce apoptosis of SFs and ameliorate the rheumatoid joint, implicating an enhancement of the p73-dependent apoptotic mechanism as a pharmacological strategy in the RA therapy.

Highlights

Wild-type p53 can prevent the onset and development of tumor cells through activating the suppressive responses, its function loss due to a dominantnegative regulation from the mutant counterpart is a common feature in human cancers [1, 2]
We examined whether intra-articular (i.a.) administration of p53-derived hybrid peptides to activate p73 can induce apoptosis of synovial fibroblasts (SFs) by using adenoviral vectors encoding 37 amino acid (Ad37AA), a p53-derived hybrid peptide capable of activating p73, to transduce SFs in vitro and inject collagen-induced arthritis (CIA) joints in vivo
The ability of RASFs to survive in the environment rich in apoptosis-inducing factors resembles the phenotype www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget of selected tumor cells [6]

Summary

Introduction

Wild-type p53 can prevent the onset and development of tumor cells through activating the suppressive responses, its function loss due to a dominantnegative regulation from the mutant counterpart is a common feature in human cancers [1, 2]. Our previous experiments demonstrate that wild-type p53 is inactivated by its mutant counterpart in SFs from RA patients and collagen-induced arthritis (CIA) rats [8]. We examined whether transducing SFs and injecting CIA joints with the adenoviral vector encoding 37AA (Ad37AA) can dissociate the binding with iASPP to activate p73 and induce apoptosis. Higher expression of p53 upregulated modulator of apoptosis (PUMA) and Bax with enhanced apoptosis were found in Ad37AA-transduced SFs with lower iASPP-associated p73 levels, and silencing p73 abrogated the up-regulation of PUMA and Bax. Articular indexes and histologic scores were reduced in Ad37AA-injected CIA joints with decreased SF densities, increased apoptotic cell numbers, and higher PUMA expression levels

Methods

Results

Conclusion