Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum-associated degradation system
Alterations in the glycoform of cisplatin-resistant human carcinoma cells are caused by defects in the endoplasmic reticulum-associated degradation system
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DOI：
10.1016/j.canlet.2008.05.019
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发表时间：
2008-11-08
期刊：
影响因子：
9.7
通讯作者：
Nishimura, Shin-Ichiro
中科院分区：
文献类型：
--
作者：
Nakagawa, Hiroaki;Ohira, Miki;Nishimura, Shin-Ichiro
顺铂，顺式二胺铂-(II)二氯化物(CDDP)，是治疗各种癌症最常见和最有价值的化疗试剂之一。然而，众所周知，肿瘤细胞对这种抗癌试剂的治疗产生了获得性或内在的抵抗力。尽管使用遗传和蛋白质组学方法进行了大量努力，但 CDDP 耐药性的机制仍不清楚。在本研究中，我们报告了 CDDP 耐药肿瘤细胞（从 KB-3-1 人类癌细胞获得的 KCP-4 细胞系）中糖蛋白 N-聚糖的结构发生了巨大的变化。有人认为，CDDP 抗性细胞表现出一种高甘露糖型聚糖的增加，特别是 M8.1。众所周知，这种 N-聚糖是未折叠蛋白从内质网运输到溶酶体的标签，这一过程称为内质网相关降解 (ERAD) 系统。从 KCP-4 细胞系获得的回复体细胞 (KCP-4R) 显示出与亲代细胞几乎相同的糖型谱，表明肿瘤细胞中的 N-聚糖生物合成明显对应于 CDDP 敏感性的改变。使用 cDNA 微阵列进行基因表达分析显示，耐药细胞中主要组织相容性复合体 (MHC) 蛋白的表达下降。 MHC 蛋白与溶酶体降解的蛋白形成复合物并呈现在细胞表面。这些结果表明 KCP-4 细胞中的 CDDP 耐受是由 ERAD 系统缺陷引起的。 (C) 2008 Elsevier Ireland Ltd. 保留所有权利。
Cisplatin, cis-diamineplatinum-(II) dichloride (CDDP), is one of the most common and valuable chemotherapeutic reagents for various cancers. However, it is well known that tumor cells gain acquired or intrinsic resistance to treatment by this anti-cancer reagent. In spite of extensive efforts using genetic and proteomic approaches, the mechanism underlying CDDP resistance remains unclear. In the present study, we report drastic structural changes in the N-glycans of glycoproteins in CDDP-resistant tumor cells (the KCP-4 cell line obtained from KB-3-1 human carcinoma cells). It was suggested that the CDDP-resistant cells exhibited an increase in one of the high-mannose-type glycans, particularly M8.1. This N-glycan is well known as a tag for the transport of unfolded protein from the endoplasmic reticulum to the lysosome, a process known as endoplasmic reticulum-associated degradation (ERAD) system. The revertant cells (KCP-4R) obtained from the KCP-4 cell line showed almost the same glycoform profile as that of the parental cells, suggesting that N-glycan biosynthesis in tumor cells clearly corresponds to the alteration in the sensitivity against CDDP. Gene expression analysis using a cDNA microarray showed a decrease in the expression of major histocompatibility complex (MHC) proteins in the resistant cells. MHC proteins form a complex with lysosome-degradated proteins and are presented on the cell surface. These results suggest that CDDP tolerance in KCP-4 cells is caused by a defect in the ERAD system. (C) 2008 Elsevier Ireland Ltd. All rights reserved.