Huo Yi, Zong Zhaoyun, Wang Qingtao, Zhang Zhenyu, Deng Haiteng
MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China.
Oncotarget. 2017 Nov 18;8(64):107452-107461. doi: 10.18632/oncotarget.22488. eCollection 2017 Dec 8.
Tumor cells frequently evolved resistance to cisplatin that greatly compromises the efficacy of chemotherapy. Identification of the mechanisms underlying drug resistance is important for developing new therapeutic approaches. ISG15 is found to be elevated in many human carcinomas and cancer cell lines. Here, we identified that the expressions of ISG15 and ISG15-conjugating system were downregulated in drug resistant A549/DDP cells compared to drug sensitive A549 cells. Silencing of ISG15 robustly elevated the resistance to cisplatin, suggesting ISG15 plays an important role in cisplatin resistance. Quantitative proteomics identified 1296 differentially expressed proteins between the control and ISG15 knockdown cells, showing that ISG15 silencing upregulated proteins in p53 pathway, adherens junction and nucleotide excision repair (NER) pathway. We also found that ISG15 silencing induced cell cycle arrest through stabilizing p53 and increasing HnRNP K expression, which allowed the prolonged time for cells to repair cisplatin-damaged DNA. Taken together, we proved that ISG15 downregulation activated the DNA damage/repair pathway to enhance cisplatin resistance in tumor cells.
肿瘤细胞常常对顺铂产生耐药性，这极大地损害了化疗效果。确定耐药背后的机制对于开发新的治疗方法很重要。研究发现，ISG15在许多人类癌症和癌细胞系中表达上调。在此，我们发现与药物敏感的A549细胞相比，耐药的A549/DDP细胞中ISG15及其缀合系统的表达下调。敲低ISG15可显著提高对顺铂的耐药性，表明ISG15在顺铂耐药中起重要作用。定量蛋白质组学鉴定出对照细胞和ISG15敲低细胞之间有1296种差异表达蛋白，表明敲低ISG15会上调p53通路、黏着连接和核苷酸切除修复（NER）通路中的蛋白。我们还发现，敲低ISG15通过稳定p53和增加HnRNP K表达诱导细胞周期停滞，这使得细胞有更长时间修复顺铂损伤的DNA。综上所述，我们证明ISG15下调激活了DNA损伤/修复通路，从而增强了肿瘤细胞对顺铂的耐药性。
