Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
复制标题
DOI：
10.1007/s10637-012-9902-y
复制
发表时间：
2013-06-01
影响因子：
3.4
通讯作者：
Rickardson, Linda
中科院分区：
文献类型：
--
作者：
Felth, Jenny;Lesiak-Mieczkowska, Karolina;Rickardson, Linda
藤黄酸（GA），显示对各种肿瘤细胞的细胞毒性，并已被证明会影响许多重要的细胞信号通路。在目前的工作中，我们研究了GA的作用机制，通过分析药物诱导的基因表达谱的变化，并确定了GA和衍生物二氢GA作为可能的抑制剂的泛素-蛋白酶体系统（UPS）。GA和二氢GA都抑制细胞中蛋白酶体的功能，导致多聚泛素复合物的积累。体外实验表明，GA和二氢GA抑制20 S糜蛋白酶活性和GA和二氢GA对蛋白酶体功能的抑制作用对应于凋亡诱导和细胞死亡。总之，我们的研究结果表明，GA和二氢GA通过抑制UPS发挥其细胞毒性活性，特别是通过作为20 S蛋白酶体的胰凝乳蛋白酶活性的抑制剂。
Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.