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Title: Oxidation resistance 1 is a novel senolytic target

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 stressmore » 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.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [3];  [3];  [1];  [1];  [4];  [5];  [6];  [7];  [8]
+ Show Author Affiliations
  1. Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Pharmaceutical Sciences, College of Pharmacy
  2. Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Pharmaceutical Sciences, College of Pharmacy; Soochow University School of Medicine, Suzhou (China). Hematology Center of Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology
  3. Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Biochemistry and Molecular Biology, College of Medicine
  4. Unity Biotechnology, Brisbane, CA (United States)
  5. The Buck Institute for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  6. Hematology Center of Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou China
  7. Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Pharmaceutical Sciences, College of Pharmacy; Univ. of Florida, Gainesville, FL (United States). Dept. of Medicinal Chemistry, College of Pharmacy
  8. Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Pharmaceutical Sciences, College of Pharmacy; Univ. of Florida, Gainesville, FL (United States). Dept. of Pharmocodynamics, College of Pharmacy
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); University of Arkansas for Medical Sciences Proteomics Core Facility
OSTI Identifier:
1559794
Grant/Contract Number:  
AC02-05CH11231; P20GM109005; R01CA122023; R01CA219836; R56AG056372; P20GM103429; P20GM121293; S10OD018445
Resource Type:
Accepted Manuscript
Journal Name:
Aging Cell
Additional Journal Information:
Journal Volume: 17; Journal Issue: 4; Journal ID: ISSN 1474-9718
Publisher:
Anatomical Society - Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cellular senescence, OXR1, piperlongumine, reactive oxygen species

Citation Formats

Zhang, Xin, Zhang, Suping, Liu, Xingui, Wang, Yingying, Chang, Jianhui, Zhang, Xuan, Mackintosh, Samuel G., Tackett, Alan J., He, Yonghan, Lv, Dongwen, Laberge, Remi-Martin, Campisi, Judith, Wang, Jianrong, Zheng, Guangrong, and Zhou, Daohong. Oxidation resistance 1 is a novel senolytic target. United States: N. p., 2018. Web. doi:10.1111/acel.12780.
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Zhang, Xin, Zhang, Suping, Liu, Xingui, Wang, Yingying, Chang, Jianhui, Zhang, Xuan, Mackintosh, Samuel G., Tackett, Alan J., He, Yonghan, Lv, Dongwen, Laberge, Remi-Martin, Campisi, Judith, Wang, Jianrong, Zheng, Guangrong, & Zhou, Daohong. Oxidation resistance 1 is a novel senolytic target. United States. https://doi.org/10.1111/acel.12780
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Zhang, Xin, Zhang, Suping, Liu, Xingui, Wang, Yingying, Chang, Jianhui, Zhang, Xuan, Mackintosh, Samuel G., Tackett, Alan J., He, Yonghan, Lv, Dongwen, Laberge, Remi-Martin, Campisi, Judith, Wang, Jianrong, Zheng, Guangrong, and Zhou, Daohong. Tue . "Oxidation resistance 1 is a novel senolytic target". United States. https://doi.org/10.1111/acel.12780. https://www.osti.gov/servlets/purl/1559794.
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@article{osti_1559794,
title = {Oxidation resistance 1 is a novel senolytic target},
author = {Zhang, Xin and Zhang, Suping and Liu, Xingui and Wang, Yingying and Chang, Jianhui and Zhang, Xuan and Mackintosh, Samuel G. and Tackett, Alan J. and He, Yonghan and Lv, Dongwen and Laberge, Remi-Martin and Campisi, Judith and Wang, Jianrong and Zheng, Guangrong and Zhou, Daohong},
abstractNote = {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.},
doi = {10.1111/acel.12780},
journal = {Aging Cell},
number = 4,
volume = 17,
place = {United States},
year = {2018},
month = {5}
}
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https://doi.org/10.1111/acel.12780
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journal, April 2015

  • Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar
  • Aging Cell, Vol. 14, Issue 4
  • DOI: 10.1111/acel.12344

Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors
journal, March 2016

  • Zhu, Yi; Tchkonia, Tamara; Fuhrmann-Stroissnigg, Heike
  • Aging Cell, Vol. 15, Issue 3
  • DOI: 10.1111/acel.12445

Senescent intimal foam cells are deleterious at all stages of atherosclerosis
journal, October 2016

Aging, Cellular Senescence, and Cancer
journal, February 2013

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases
journal, January 2016

  • Davalli, Pierpaola; Mitic, Tijana; Caporali, Andrea
  • Oxidative Medicine and Cellular Longevity, Vol. 2016
  • DOI: 10.1155/2016/3565127

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse
journal, December 2016

BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation
journal, June 2011

Senescence and apoptosis: dueling or complementary cell fates?
journal, October 2014

  • Childs, Bennett G.; Baker, Darren J.; Kirkland, James L.
  • EMBO reports, Vol. 15, Issue 11
  • DOI: 10.15252/embr.201439245

New agents that target senescent cells: the flavone, fisetin, and the BCL-X<sub>L</sub> inhibitors, A1331852 and A1155463
journal, March 2017

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    • Nature Reviews Chemistry, Vol. 3, Issue 7
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    Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis
    journal, January 2020

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