Role of Na+, K+-ATPase alpha1 subunit in the intracellular accumulation of cisplatin.
Role of Na+, K+-ATPase alpha1 subunit in the intracellular accumulation of cisplatin.
复制标题
Na , K -ATPase α1 亚基在顺铂细胞内积累中的作用。
DOI：
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发表时间：
2006
影响因子：
3
通讯作者：
Y. Takeuchi
中科院分区：
文献类型：
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作者：
S. Kishimoto;Y. Kawazoe;Mako Ikeno;Mizuha Saitoh;Yukari Nakano;Y. Nishi;S. Fukushima;Y. Takeuchi
本研究旨在确定是什么调节细胞内顺铂（CDDP）的积累，以及CDDP耐药细胞系的膜组分发生了什么变化。CDDP耐药大鼠肝癌细胞系H4-II-E/CDDP与亲本H4-II-E细胞相比，细胞内铂积累显著减少，但两种细胞系之间CDDP外排量没有差异。在这项研究中，我们研究了主动转运的功能变化对H4-II-E/CDDP细胞的CDDP抗性的贡献。与抗性细胞相比，低温或ATP耗尽明显降低了亲本细胞中铂的积累。此外，Na+， K+- atp酶抑制剂瓦巴因和K+通道抑制剂四乙基铵减少亲本细胞中铂的积累，但没有改变耐药细胞中的积累。两性霉素B，一种抗真菌剂，使耐药细胞内铂的积累增加到与亲本细胞相同的水平。Western blot分析显示，与亲本细胞相比，耐药细胞中Na+， K+-ATPase α 1亚基的表达减少，但两种细胞系之间β 1亚基的表达没有差异。此外，暴露于CDDP 24小时后，H4-II-E的Na+， K+- atp酶α 1亚基降低。这些结果表明，Na+， K+- atp酶依赖的CDDP主动转运不会发生在耐药细胞中，此外，我们的研究结果首次证明Na+， K+- atp酶α 1亚基在CDDP转运中起重要作用。
The present study was undertaken to identify what regulates intracellular cisplatin (CDDP) accumulation and what changes in membrane fraction of CDDDP-resistant cell line. The CDDP-resistant rat hepatoma cell line, H4-II-E/CDDP, shows a significant decrease in intracellular platinum accumulation compared with parental H4-II-E cells, although there was no difference in the efflux of CDDP between these two cell lines. In this study, we examined the contribution of functional change in active transport to the CDDP resistance of H4-II-E/CDDP cells. Compared with the resistant cells, platinum accumulation in the parental cells was clearly decreased by low temperature or ATP depletion. In addition, the Na+, K+-ATPase inhibitor ouabain and the K+ channel inhibitor tetraethylammonium decreased platinum accumulation in parental cells but did not change the accumulation in resistant cells. Amphotericin B, an antifungal agent, increased the intracellular platinum accumulation in resistant cells to the same level as in parent cells. Western blot analysis demonstrated that the Na+, K+-ATPase alpha1 subunit was reduced in resistant cells compared with the parental cells, although there was no difference in the expression of the beta1 subunit between the two cell lines. Furthermore, the Na+, K+-ATPase alpha1 subunit of H4-II-E was decreased following a 24-h exposure to CDDP. These results suggest that Na+, K+-ATPase-dependent active transport of CDDP does not occur in resistant cells, and, furthermore, our findings provide the first evidence that the Na+, K+-ATPase alpha1 subunit plays an important role in the transport of CDDP.