Kiguchi Kazushige, Iwamori Yuriko, Suzuki Nao, Kobayashi Yoichi, Ishizuka Bunpei, Ishiwata Isamu, Kita Tsunekazu, Kikuchi Yoshihiro, Iwamori Masao
Department of Obstetrics and Gynecology, St Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
Cancer Sci. 2006 Dec;97(12):1321-6. doi: 10.1111/j.1349-7006.2006.00326.x. Epub 2006 Sep 21.
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 microg/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.
将具有抗癌药物敏感性的人卵巢癌来源的KF28细胞中的转运蛋白基因和脂质，与耐药细胞（紫杉醇耐药的KF28TX、顺铂耐药的KFr13以及紫杉醇和顺铂耐药的KFr13TX）中的进行比较，以确定抗癌药物耐药所需的分子。与先前的报道一致，紫杉醇耐药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在糖鞘脂方面存在明显差异。虽然葡萄糖神经酰胺是敏感细胞中的主要糖脂（83.0%），但无论耐药是针对紫杉醇还是顺铂，半乳糖神经酰胺、乳糖神经酰胺，尤其是Gb(3)神经酰胺在所有耐药细胞中均有特征性增加，占总糖鞘脂的65 - 84%。GM3在敏感细胞中的含量为0.04微克/毫克干重，在紫杉醇耐药细胞中增加了两倍，但在顺铂耐药细胞中不存在。已证明糖脂组成的改变是由于各自糖基转移酶基因表达的增强或抑制所致。此外，敏感细胞中神经酰胺单己糖苷的神经酰胺部分占非羟基脂肪酸的83%，而在耐药细胞中占α - 羟基脂肪酸的67 - 74%。因此，发现含有α - 羟基脂肪酸的Gb(3)神经酰胺的细胞在紫杉醇和顺铂存在的情况下能选择性存活，并且揭示了糖脂结构的修饰与抗癌药物耐药相关。
