Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:115413-115419. https://doi.org/10.18632/oncotarget.23268

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Abstract

Shih-Yao Chen1, Ai-Li Shiau2, Chao-Liang Wu3 and Chrong-Reen Wang1

1Section of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan

2Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan

3Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

Correspondence to:

Chrong-Reen Wang, email: wangcr@mail.ncku.edu.tw

Keywords: apoptosis; p53-derived hybrid peptide; p73; rheumatoid arthritis; synovial fibroblast

Received: July 07, 2017    Accepted: December 03, 2017    Published: December 15, 2017

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.


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