JWA reverses cisplatin resistance via the CK2-XRCC1 pathway in human gastric cancer cells
JWA reverses cisplatin resistance via the CK2-XRCC1 pathway in human gastric cancer cells
复制标题
JWA 通过 CK2-XRCC1 通路逆转人胃癌细胞中的顺铂耐药性
DOI：
10.1038/cddis.2014.517
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发表时间：
2014-12-01
影响因子：
9
通讯作者：
Zhou, J.
中科院分区：
文献类型：
--
作者：
Xu, W.;Chen, Q.;Zhou, J.
胃癌是中国第三大常见恶性肿瘤，中位5年生存率仅为20%。顺铂已被用于包括胃癌在内的几种类型癌症的一线癌症治疗。然而，患者通常具有原发性耐药或出现获得性耐药，导致癌症复发并降低生存率。最近，我们证明了碱基切除修复蛋白XRCC 1及其上游调控因子JWA在胃癌组织中的表达降低与辅助一线铂类化疗的显著生存益处相关，以及XRCC 1在顺铂耐药胃癌细胞的DNA修复中发挥重要作用。在本研究中，我们证明了JWA在顺铂诱导的DNA损伤和获得的顺铂耐药在五个细胞培养模型中的作用：胃上皮细胞GES-1，顺铂敏感的胃癌细胞系BGC 823和SGC 7901，顺铂耐药的胃癌细胞系BGC 823/DDP和SGC 7901/DDP。我们的研究结果表明，在正常胃上皮细胞中，JWA是顺铂诱导的双链断裂（DSB）后通过XRCC 1进行DNA修复所必需的。然而，在胃癌细胞中，JWA通过调节DNA损伤诱导的细胞凋亡来增强顺铂诱导的细胞死亡。顺铂耐药细胞中JWA的蛋白表达显着降低，并导致顺铂耐药。有趣的是，JWA上调XRCC 1在正常细胞中的表达，JWA通过促进XRCC 1在顺铂耐药胃癌细胞中的降解而下调XRCC 1的表达。此外，由于XRCC 1的518 S/519 T/523 T残基发生突变，JWA对XRCC 1的负调控作用被阻断，提示CK 2激活的518 S/519 T/523 T磷酸化是JWA对XRCC 1调控的关键点。总之，我们首次报道了JWA通过CK 2-P-XRCC 1-XRCC 1通路调节顺铂诱导的DNA损伤和凋亡，表明了逆转胃癌顺铂耐药的假定药物靶点。
Gastric cancer is the third most common malignancy in China, with a median 5-year survival of only 20%. Cisplatin has been used in first-line cancer treatment for several types of cancer including gastric cancer. However, patients are often primary resistant or develop acquired resistance resulting in relapse of the cancer and reduced survival. Recently, we demonstrated that the reduced expression of base excision repair protein XRCC1 and its upstream regulator JWA in gastric cancerous tissues correlated with a significant survival benefit of adjuvant first-line platinum-based chemotherapy as well as XRCC1 playing an important role in the DNA repair of cisplatin-resistant gastric cancer cells. In the present study, we demonstrated the role of JWA in cisplatin-induced DNA lesions and aquired cisplatin resistance in five cell-culture models: gastric epithelial cells GES-1, cisplatin-sensitive gastric cancer cell lines BGC823 and SGC7901, and the cisplatin-resistant gastric cancer cell lines BGC823/DDP and SGC7901/DDP. Our results indicated that JWA is required for DNA repair following cisplatin-induced double-strand breaks (DSBs) via XRCC1 in normal gastric epithelial cells. However, in gastric cancer cells, JWA enhanced cisplatin-induced cell death through regulation of DNA damage-induced apoptosis. The protein expression of JWA was significantly decreased in cisplatin-resistant cells and contributed to cisplatin resistance. Interestingly, as JWA upregulated XRCC1 expression in normal cells, JWA downregulated XRCC1 expression through promoting the degradation of XRCC1 in cisplatin-resistant gastric cancer cells. Furthermore, the negative regulation of JWA to XRCC1 was blocked due to the mutation of 518S/519T/523T residues of XRCC1, and indicating that the CK2 activated 518S/519T/523T phosphorylation is a key point in the regulation of JWA to XRCC1. In conclusion, we report for the first time that JWA regulated cisplatin-induced DNA damage and apoptosis through the CK2-P-XRCC1-XRCC1 pathway, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.