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首页> 外文期刊>The Journal of toxicological sciences >Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells.
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Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells.

机译：Hsp90抑制剂格尔德霉素及其类似物对PC12细胞神经酰胺代谢和细胞毒性的影响。

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摘要

The inhibitors of heat shock protein-90 (Hsp90), geldanamycin (GA) and 17-(allylamino)-17-desmethoxygeldanamycin, show various cellular effects including destabilization of Hsp90 clients and expression of other chaperones, etc. and modulate cytotoxicity depending on cell types and stimuli. In this study, we investigated the effects of Hsp90 inhibitors on survival of PC12 cells with and without cytotoxic stimuli including orthovanadate, Na(3)VO(4). Treatment with Hsp90 inhibitors at 2 μM for 16 hr did not cause cell detachment and leakage of lactate dehydrogenase, and at concentrations greater than 5 μM resulted in cytotoxicity. The inhibitors at 2 μM enhanced the cytotoxicity of 1 mM Na(3)VO(4), and did not protect PC12 cells at any concentrations against Na(3)VO(4). Next, the effects of Hsp90 inhibitors on the intracellular metabolism of ceramide and arachidonic acid (AA) were examined, since these processes also regulate cytotoxicity. In cells treated with 4-nitrobenzo-2-oxa-1,3-diazole (NBD)-labeled C6-ceramide, Hsp90 inhibitors reduced the formation of NBD-glucosylceramide and Na(3)VO(4)-induced formation of NBD-caproic acid, a counterpart of sphingosine, without affecting other metabolites including NBD-sphingomyelin. GA treatment did not change the amounts of AA released in PC12 cells with and without Na(3)VO(4). In HeLa cells, however, GA treatment decreased the release of AA via cytosolic phospholipase A(2)α's activation probably because of dysfunctional Hsp90 clients. Our results suggest the possible involvement of ceramide metabolism, not AA release, in GA-induced cytotoxicity in PC12 cells.
机译：热休克蛋白90（Hsp90），格尔德霉素（GA）和17-（烯丙胺基）-17-去甲氧基格尔德霉素的抑制剂表现出多种细胞效应，包括Hsp90客户的不稳定和其他分子伴侣的表达等，并根据细胞调节细胞毒性类型和刺激。在这项研究中，我们调查了Hsp90抑制剂对PC12细胞存活的影响，无论是否存在细胞毒性刺激物，包括原钒酸盐，Na（3）VO（4）。用2μM的Hsp90抑制剂处理16小时不会引起细胞脱离和乳酸脱氢酶的泄漏，并且浓度大于5μM的细胞会导致细胞毒性。在2μM的抑制剂可以增强1 mM Na（3）VO（4）的细胞毒性，并且不能以任何浓度保护PC12细胞免受Na（3）VO（4）的作用。接下来，检查了Hsp90抑制剂对神经酰胺和花生四烯酸（AA）细胞内代谢的影响，因为这些过程还调节细胞毒性。在用4-硝基苯并-2-氧杂-1,3-二唑（NBD）标记的C6-神经酰胺处理的细胞中，Hsp90抑制剂减少了NBD-葡萄糖基神经酰胺和Na（3）VO（4）诱导的NBD-的形成。己酸，鞘氨醇的对应物，不影响其他代谢产物，包括NBD-鞘磷脂。 GA处理不会改变有和没有Na（3）VO（4）的PC12细胞中AA的释放量。然而，在HeLa细胞中，GA治疗通过细胞溶质磷脂酶A（2）α的活化减少了AA的释放，这可能是由于Hsp90客户功能异常。我们的结果表明，GA诱导PC12细胞的细胞毒性可能涉及神经酰胺代谢而不是AA释放。

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