Elevated expression of vacuolar proton pump genes and cellular pH in cisplatin resistance
Elevated expression of vacuolar proton pump genes and cellular pH in cisplatin resistance
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DOI：
10.1002/ijc.1418
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发表时间：
2001-09-15
影响因子：
6.4
通讯作者：
Kohno, K
中科院分区：
文献类型：
--
作者：
Murakami, T;Shibuya, I;Kohno, K
v - atp酶是一种质子转运酶，不仅存在于许多胞内细胞器中，而且存在于许多真核细胞的质膜中。利用差分显示，我们已经鉴定出一个质子泵亚基基因ATP6C作为顺铂诱导基因。Northern blot分析表明，顺铂治疗可诱导亚基其他成员的表达。质子泵基因表达在3个独立的顺铂耐药细胞系中也上调，但在长春新碱或依托泊苷耐药细胞系中没有上调。顺铂耐药细胞的细胞PH值明显高于敏感亲本细胞。在体外，顺铂的dna结合活性在酸性条件下显著增加，表明顺铂的细胞毒性受到细胞ph的调节。此外，质子泵抑制剂巴菲霉素可以协同增强顺铂的细胞毒性，而对依托泊苷或喜树碱则没有作用。这些结果表明，细胞pH值是顺铂有效化疗的关键参数之一。(C) 2001 Wiley-Liss, Inc。
V-ATPases are proton-translocating enzymes, which are found not only in numerous intracellular organelles but also in the plasma membranes of many eukaryotic cells. Using differential display, we have identified one of the proton pump subunit genes, ATP6C, as a cisplatin-inducible gene. Northern blot analysis demonstrated that expression of other members of the subunit is inducible by cisplatin treatment. Proton pump gene expression is also upregulated in 3 independent cisplatin-resistant cell lines but not in vincristine- or etoposide-resistant cell lines. Cellular PH was significantly higher in cisplatin-resistant cells than in sensitive parental cells. In vitro DNA-binding activity of cisplatin was markedly increased in acidic conditions, suggesting that the cytotoxicity of cisplatin is modulated by cellular pH. Furthermore, the proton pump inhibitor bafilomycin can synergistically potentiate the cytotoxicity of cisplatin but not of etoposide or camptothecin. These results indicate that cellular pH is one of the critical parameters for effective cancer chemotherapy with cisplatin. (C) 2001 Wiley-Liss, Inc.