Open AccessOxidation resistance 1 is a novel senolytic target
Author(s) -
Zhang Xin,
Zhang Suping,
Liu Xingui,
Wang Yingying,
Chang Jianhui,
Zhang Xuan,
Mackintosh Samuel G.,
Tackett Alan J.,
He Yonghan,
Lv Dongwen,
Laberge RemiMartin,
Campisi Judith,
Wang Jianrong,
Zheng Guangrong,
Zhou Daohong
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12780
Subject(s) - downregulation and upregulation , gene knockdown , reactive oxygen species , biology , oxidative stress , microbiology and biotechnology , catalase , antioxidant , biochemistry , cancer research , chemistry , apoptosis , gene
Summary The selective depletion of senescent cells ( SC s) by small molecules, termed senolytic agents, is a promising therapeutic approach for treating age‐related diseases and chemotherapy‐ and radiotherapy‐induced side effects. Piperlongumine ( PL ) was recently identified as a novel senolytic agent. However, its mechanism of action and molecular targets in SC s was unknown and thus was investigated. Specifically, we used a PL ‐based chemical probe to pull‐down PL ‐binding proteins from live cells and then mass spectrometry‐based proteomic analysis to identify potential molecular targets of PL in SC s. One prominent target was oxidation resistance 1 ( OXR 1), an important antioxidant protein that regulates the expression of a variety of antioxidant enzymes. We found that OXR 1 was upregulated in senescent human WI 38 fibroblasts. PL bound to OXR 1 directly and induced its degradation through the ubiquitin‐proteasome system in an SC ‐specific manner. The knockdown of OXR 1 expression by RNA interference significantly increased the production of reactive oxygen species in SC s in conjunction with the downregulation of antioxidant enzymes such as heme oxygenase 1, glutathione peroxidase 2, and catalase, but these effects were much less significant when OXR 1 was knocked down in non‐ SC s. More importantly, knocking down OXR 1 selectively induced apoptosis in SC s and sensitized the cells to oxidative stress caused by hydrogen peroxide. These findings provide new insights into the mechanism by which SC s are highly resistant to oxidative stress and suggest that OXR 1 is a novel senolytic target that can be further exploited for the development of new senolytic agents.