Bcl-2-associated X protein is the main mediator of manumycin a-induced apoptosis in anaplastic thyroid cancer cells.
Bcl-2-associated X protein is the main mediator of manumycin a-induced apoptosis in anaplastic thyroid cancer cells.
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DOI：
10.1210/jc.2004-2106
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发表时间：
2005-06
期刊：
影响因子：
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通讯作者：
Jingxuan Pan;Huizhi Huang;Lily Sun;B. Fang;S. J. Yeung
中科院分区：
文献类型：
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作者：
Jingxuan Pan;Huizhi Huang;Lily Sun;B. Fang;S. J. Yeung
我们以前证明，紫杉醇和manumycin A，法尼基转移酶抑制剂，增强未分化甲状腺癌（ATC）细胞凋亡的组合。然而，manumycin诱导细胞凋亡的机制尚未完全了解。在本研究中，我们发现在用manumycin或manumycin加紫杉醇处理后，线粒体超微结构发生凝聚。已知的电压依赖性阴离子通道抑制剂邦克酸和环孢菌素A未能抑制由manumycin或manumycin加紫杉醇诱导的细胞色素c释放，这表明线粒体通透性转换孔不参与。我们还发现，manumycin诱导的Bcl-2相关的X蛋白（Bax），细胞色素c释放的另一种可能的介质，从细胞质到线粒体的易位。沉默Bax与特定的小干扰RNA阻断manumycin诱导的线粒体凝聚和细胞色素c的释放，认为manumycin诱导的细胞凋亡对Bax的依赖。使用二元腺病毒载体系统，我们发现Bax的过表达增强manumycin诱导的ATC细胞凋亡，manumycin和Bax的过表达的组合增加了对裸鼠ATC异种移植物生长的抑制。因此，我们得出结论，manumycin诱导的ATC细胞凋亡主要是由Bax介导的，增加Bax表达可能使ATC细胞对manumycin敏感。
We previously demonstrated that the combination of paclitaxel and manumycin A, a farnesyltransferase inhibitor, enhanced apoptosis of anaplastic thyroid cancer (ATC) cells. However, the mechanism of the manumycin-induced apoptosis is not fully understood. In this study, we discovered that mitochondrial ultrastructure condensation occurred after treatment with manumycin or manumycin plus paclitaxel. Bongkrekic acid and cyclosporin A, which are known inhibitors of the voltage-dependent anion channel, failed to inhibit cytochrome c release induced by manumycin or manumycin plus paclitaxel, suggesting that mitochondrial permeability transition pores were not involved. We also found that manumycin induced translocation of Bcl-2-associated X protein (Bax), another possible mediator of cytochrome c release, from the cytosol to the mitochondria. Silencing Bax with a specific small interfering RNA blocked manumycin-induced mitochondrial condensation and cytochrome c release, arguing the dependence of manumycin-induced apoptosis on Bax. Using a binary adenoviral vector system, we found that overexpression of Bax enhanced manumycin-induced apoptosis of ATC cells, and the combination of manumycin and overexpression of Bax increased inhibition of ATC xenograft growth in nude mice. Thus, we concluded that manumycin-induced apoptosis in ATC cells was primarily mediated by Bax and that increasing Bax expression may sensitize ATC cells to manumycin.