Xu Xiulong, Rao Geetha, Li Yi
Institute of Comparative Medicine, Yangzhou University, Jiangsu Province, Yangzhou 225009, P.R. China.
College of Veterinary Medicine, Yangzhou University, Jiangsu Province, Yangzhou 225009, P.R. China.
Oncotarget. 2016 Sep 13;7(37):59220-59235. doi: 10.18632/oncotarget.11042.
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.
MICA/B（主要组织相容性抗原相关链A和B）和Rae I是免疫受体NKG2D的应激诱导配体。基因毒性应激和DNA损伤诱导NKG2D配体表达的机制仍未完全了解。在此，我们报告，别嘌呤醇对黄嘌呤氧化还原酶（XOR）活性的抑制或基因敲低对XOR表达的抑制，消除了三种肿瘤细胞系中基因毒性应激诱导的MICA/B和Rae I表达。在原位同基因乳腺癌小鼠模型中，XOR敲低也阻断了吉西他滨介导的抗肿瘤活性。作为嘌呤分解代谢途径中的限速酶，XOR产生两种终产物，尿酸和活性氧（ROS）。清除ROS对基因毒性药物诱导的MICA/B表达影响不大，但适度抑制辐射诱导的MICA/B表达。外源性尿酸（以尿酸钠形式）通过激活丝裂原活化蛋白激酶（MAP激酶）途径诱导MICA/B表达。别嘌呤醇阻断基因毒性应激诱导的MAP激酶激活。我们的研究为基因毒性应激诱导的MAP激酶途径激活提供了机制性见解，并表明XOR是基因毒性应激诱导的NKG2D配体表达和吉西他滨介导的抗肿瘤活性所必需的。
