Characteristic expression of globotriaosyl ceramide in human ovarian carcinoma-derived cells with anticancer drug resistance
Characteristic expression of globotriaosyl ceramide in human ovarian carcinoma-derived cells with anticancer drug resistance
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DOI：
10.1111/j.1349-7006.2006.00326.x
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发表时间：
2006-12-01
期刊：
影响因子：
5.7
通讯作者：
Iwamori, Masao
中科院分区：
文献类型：
--
作者：
Kiguchi, Kazushige;Iwamori, Yuriko;Iwamori, Masao
将人卵巢癌来源的具有抗癌药物敏感特性的KF 28细胞中的转运蛋白基因和脂质与耐药细胞、紫杉醇耐药KF 28 TX、顺铂耐药KFr 13以及紫杉醇和顺铂耐药KFr 13 TX中的转运蛋白基因和脂质进行比较，以鉴定抗癌药物耐药所需的分子。根据以前的报道，紫杉醇和顺铂耐药分别与多药耐药1和胆汁酸输出泵以及多药耐药相关蛋白2基因的表达密切相关。此外，我们发现敏感细胞和耐药细胞之间的鞘糖脂存在明显差异。尽管GlcCer是敏感细胞中的主要糖脂（83.0%），但GalCer、LacCer，特别是Gb（3）Cer在所有耐药细胞中特征性地增加，无论是对紫杉醇还是顺铂的耐药，并且占总鞘糖脂的65-84%。GM 3，这是目前在敏感细胞中的0.04微克/毫克干重，显示了紫杉醇耐药细胞的两倍增加，但在顺铂耐药细胞中不存在。糖脂组成的改变被证明是由于增强或抑制各自的糖转移酶基因的表达。另外，神经酰胺单己糖苷的神经酰胺部分在敏感细胞中构成83%的非羟基脂肪酸，而在抗性细胞中构成67-74%的α-羟基脂肪酸。因此，发现含有Gb（3）Cer和α-羟基脂肪酸的细胞在紫杉醇和顺铂存在下选择性存活，并且糖脂结构的修饰被揭示与抗癌药物抗性相关。
The transporter protein genes and lipids in human ovarian carcinoma-derived KF28 cells with anticancer-drug-sensitive properties were compared with those in resistant cells, taxol-resistant KF28TX, cisplatin-resistant KFr13, and taxol- and cisplatin-resistant KFr13TX, to identify the molecules required for anticancer-drug resistance. In accordance with previous reports, taxol and cisplatin resistance was closely correlated with expression of the multidrug resistance 1 and bile acid export pump, and multidrug resistance-associated protein 2 genes, respectively. In addition, we found a distinct difference in glycosphingolipids between the sensitive and resistant cells. Although GlcCer was the major glycolipid (83.0%) in sensitive cells, GalCer, LacCer and, particularly, Gb(3)Cer were characteristically increased in all resistant cells, irrespective of whether the resistance was to taxol or cisplatin, and comprised 65-84% of total glycosphingolipids. GM3, which was present at 0.04 mu g/mg dry weight in the sensitive cells, showed a twofold increase in the taxol-resistant cells, but was absent in the cisplatin-resistant cells. The altered glycolipid composition was proven to be due to enhanced or suppressed expression of the respective sugar transferase genes. In addition, the ceramide moiety of ceramide monohexoside in the sensitive cells constituted 83% of non-hydroxy fatty acids, but that in the resistant cells comprised 67-74% of alpha-hydroxy fatty acids. Thus, cells containing Gb(3)Cer with alpha-hydroxy fatty acids were found to survive selectively in the presence of taxol and cisplatin, and modification of the glycolipid structure was revealed to occur in association with anticancer-drug resistance.