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Aging Cell. 2018 Aug;17(4):e12780. doi: 10.1111/acel.12780. Epub 2018 May 15.

Oxidation resistance 1 is a novel senolytic target.

Author information

1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
2
Hematology Center of Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou, China.
3
Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
4
Unity Biotechnology, Brisbane, California.
5
The Buck Institute for Research on Aging, Novato, California.
6
Lawrence Berkeley National Laboratories, Berkeley, California.
7
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida.
8
Department of Pharmcodynamics, College of Pharmacy, University of Florida, Gainesville, Florida.

Abstract

The selective depletion of senescent cells (SCs) 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 SCs 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 SCs. One prominent target was oxidation resistance 1 (OXR1), an important antioxidant protein that regulates the expression of a variety of antioxidant enzymes. We found that OXR1 was upregulated in senescent human WI38 fibroblasts. PL bound to OXR1 directly and induced its degradation through the ubiquitin-proteasome system in an SC-specific manner. The knockdown of OXR1 expression by RNA interference significantly increased the production of reactive oxygen species in SCs 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 OXR1 was knocked down in non-SCs. More importantly, knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide. These findings provide new insights into the mechanism by which SCs are highly resistant to oxidative stress and suggest that OXR1 is a novel senolytic target that can be further exploited for the development of new senolytic agents.

KEYWORDS:

OXR1; cellular senescence; piperlongumine; reactive oxygen species

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