Oxidation resistance 1 is a novel senolytic target

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

doi:10.1111/acel.12780

Title: Oxidation resistance 1 is a novel senolytic target

Journal Article · 15 May 2018 · Aging Cell

DOI: https://doi.org/10.1111/acel.12780 · OSTI ID:1559794

Zhang, Xin ^[1]; Zhang, Suping ^[2]; Liu, Xingui ^[1]; Wang, Yingying ^[1]; Chang, Jianhui ^[1]; Zhang, Xuan ^[1]; Mackintosh, Samuel G. ^[3]; Tackett, Alan J. ^[3]; He, Yonghan ^[1]; Lv, Dongwen ^[1]; Laberge, Remi-Martin ^[4]; Campisi, Judith ^[5]; Wang, Jianrong ^[6]; Zheng, Guangrong ^[7]; Zhou, Daohong ^[8]

Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Pharmaceutical Sciences, College of Pharmacy
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
Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States). Dept. of Biochemistry and Molecular Biology, College of Medicine
Unity Biotechnology, Brisbane, CA (United States)
The Buck Institute for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Hematology Center of Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, Soochow University School of Medicine, Suzhou China
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
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

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); University of Arkansas for Medical Sciences Proteomics Core Facility

Grant/Contract Number:: AC02-05CH11231; P20GM109005; R01CA122023; R01CA219836; R56AG056372; P20GM103429; P20GM121293; S10OD018445

OSTI ID:: 1559794

Journal Information:: Aging Cell, Vol. 17, Issue 4; ISSN 1474-9718

Publisher:: Anatomical Society - WileyCopyright Statement

Country of Publication:: United States

Language:: English

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Aging, Cellular Senescence, and Cancer Campisi, Judith Annual Review of Physiology, Vol. 75, Issue 1 https://doi.org/10.1146/annurev-physiol-030212-183653	journal	February 2013
ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases Davalli, Pierpaola; Mitic, Tijana; Caporali, Andrea Oxidative Medicine and Cellular Longevity, Vol. 2016 https://doi.org/10.1155/2016/3565127	journal	January 2016
BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation Vogler, Meike; Hamali, Hassan A.; Sun, Xiao-Ming Blood, Vol. 117, Issue 26 https://doi.org/10.1182/blood-2011-03-344812	journal	June 2011
Senescence and apoptosis: dueling or complementary cell fates? Childs, Bennett G.; Baker, Darren J.; Kirkland, James L. EMBO reports, Vol. 15, Issue 11 https://doi.org/10.15252/embr.201439245	journal	October 2014
New agents that target senescent cells: the flavone, fisetin, and the BCL-X_L inhibitors, A1331852 and A1155463 Zhu, Yi; Doornebal, Ewald J.; Pirtskhalava, Tamar Aging, Vol. 9, Issue 3 https://doi.org/10.18632/aging.101202	journal	March 2017
Oxidation resistance 1 is essential for protection against oxidative stress and participates in the regulation of aging in Caenorhabditis elegans Sanada, Y.; Asai, S.; Ikemoto, A. Free Radical Research, Vol. 48, Issue 8 https://doi.org/10.3109/10715762.2014.927063	journal	June 2014

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Proteome Oxidative Modifications and Impairment of Specific Metabolic Pathways During Cellular Senescence and Aging Hamon, Marie‐Paule; Ahmed, Emad K.; Baraibar, Martín A. PROTEOMICS, Vol. 20, Issue 5-6 https://doi.org/10.1002/pmic.201800421	journal	March 2020
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Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis Stojanović, Stevan D.; Fiedler, Jan; Bauersachs, Johann European Heart Journal, Vol. 41, Issue 31 https://doi.org/10.1093/eurheartj/ehz919	journal	January 2020
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59 BASIC BIOLOGICAL SCIENCES
cellular senescence
OXR1
piperlongumine
reactive oxygen species

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