TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer.
TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer.
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TXNL1-XRCC1 通路调节顺铂诱导的细胞死亡并有助于人胃癌的耐药性
DOI：
10.1038/cddis.2014.27
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发表时间：
2014-02-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
顺铂是触发DNA交联诱导细胞死亡的细胞毒性铂化合物，并且是用于治疗几种类型的人类癌症（包括胃癌）的参考药物之一。然而，顺铂的固有或获得性耐药非常常见，并导致治疗失败。我们最近发现，胃癌组织中碱基切除修复蛋白XRCC 1（X射线修复交叉互补组1）的表达减少与辅助一线铂类化疗的显著生存益处相关。本研究利用顺铂敏感的胃癌细胞系BGC 823和顺铂耐药的胃癌细胞系BGC 823/顺铂（DDP），研究XRCC 1在顺铂诱导的DNA损伤修复和获得性顺铂耐药中的作用。我们的研究结果表明，XRCC 1蛋白表达显着增加顺铂耐药细胞和独立贡献顺铂耐药。伊立替康是另一种诱导DNA损伤的化疗药物，用于治疗顺铂治疗进展的晚期胃癌患者，发现其有效抑制XRCC 1的表达，并导致耐药细胞对顺铂的敏感性增加。我们的蛋白质组学研究进一步确定了26 S蛋白酶体的辅因子，硫氧还蛋白样蛋白1（TXNL 1），通过泛素-蛋白酶体途径下调BGC 823/DDP细胞中的XRCC 1。总之，TXNL 1-XRCC 1是一种新的调节途径，在顺铂耐药中具有独立的作用，表明了逆转胃癌顺铂耐药的假定药物靶点。
Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis-diamminedichloridoplatinum (II)(DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitin-proteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.
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影响因子：
3.7
作者：
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影响因子：
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14.9
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通讯作者：
Ménissier-de Murcia J
影响因子：
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