Oncotarget

Research Papers:

Xanthine oxidoreductase is required for genotoxic stress-induced NKG2D ligand expression and gemcitabine-mediated antitumor activity

Xiulong Xu _, Geetha Rao and Yi Li

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Oncotarget. 2016; 7:59220-59235. https://doi.org/10.18632/oncotarget.11042

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Abstract

Xiulong Xu1,2,3, Geetha Rao3, Yi Li4

1Institute of Comparative Medicine, Yangzhou University, Jiangsu Province, Yangzhou 225009, P.R. China

2College of Veterinary Medicine, Yangzhou University, Jiangsu Province, Yangzhou 225009, P.R. China

3Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL 60612, USA

4Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA

Correspondence to:

Xiulong Xu, email: xxl@yzu.edu.cn, xxu@rush.edu

Keywords: xanthine oxidoreductase, breast cancer, NKG2D ligand, uric acid, MAP kinase

Received: January 19, 2016     Accepted: July 18, 2016     Published: August 03, 2016

ABSTRACT

MICA/B (the major histocompatibility antigen-related chain A and B) and Rae I are stress-inducible ligands for the immune-receptor NKG2D. Mechanisms by which genotoxic stress and DNA damage induce the expression of NKG2D ligands remain incompletely understood. Here, we report that inhibition of xanthine oxidoreductase (XOR) activity by allopurinol or inhibition of XOR expression by gene knockdown abrogated genotoxic stress-induced expression of MICA/B and Rae I in three tumor cell lines. XOR knockdown also blocked gemcitabine-mediated antitumor activity in an orthotopic syngeneic mouse model of breast cancer. As a rate-limiting enzyme in the purine catabolic pathway, XOR generates two end-products, uric acid and reactive oxygen species (ROS). ROS scavenging had an insignificant effect on genotoxic drug-induced MICA/B expression but modestly inhibited radiation-induced MICA/B expression. Exogenous uric acid (in the form of monosodium urate) induced MICA/B expression by activating the MAP kinase pathway. Allopurinol blocked genotoxic stress-induced MAP kinase activation. Our study provides mechanistic insights into genotoxic stress-induced activation of the MAP kinase pathway and suggests that XOR is required for genotoxic stress-induced NKG2D ligand expression and gemcitabine-mediated antitumor activity.


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