Gambogic acid induced oxidative stress dependent caspase activation regulates both apoptosis and autophagy by targeting various key molecules (NF-κB, Beclin-1, p62 and NBR1) in human bladder cancer cells
Gambogic acid induced oxidative stress dependent caspase activation regulates both apoptosis and autophagy by targeting various key molecules (NF-κB, Beclin-1, p62 and NBR1) in human bladder cancer cells
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DOI：
10.1016/j.bbagen.2014.08.019
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发表时间：
2014-12-01
影响因子：
3
通讯作者：
Majumdar, Sekhar
中科院分区：
文献类型：
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作者：
Ishaq, Mohammad;Khan, Mohammad Aslam;Majumdar, Sekhar
背景：藤黄酸是一种有效的抗癌药物，已被发现对多种类型的癌细胞有效。本研究旨在探讨藤黄酸对膀胱癌细胞株T24和UMUC3的细胞毒作用及其对细胞自噬和凋亡的调节作用。方法：用藤黄酸处理膀胱癌细胞株124和UMUC3，用流式细胞仪检测细胞凋亡率，用Western blotting检测细胞自噬和凋亡相关蛋白的表达。共聚焦显微镜下观察p62和Beclin-1的共定位。结果：藤黄酸可诱导细胞产生氧自由基，并在早期激活JNK引起强烈的自噬反应，而在后期激活caspase则抑制自噬反应。活性氧介导的caspase激活导致自噬蛋白的降解，分子伴侣(Hsp90和GRP-78)和接头蛋白(p62和NBR1)的裂解。藤黄酸处理导致线粒体超极化和细胞色素c释放，并激活参与外在和内在凋亡途径的caspase。藤黄酸通过ROS介导的抑制I kappa B-α磷酸化来阻断核因子-kappaB的激活。从功能上讲，藤黄酸诱导的自噬是一种强烈的细胞存活反应，延缓了caspase的激活。结论：我们的研究为研究藤黄酸诱导膀胱癌细胞自噬和凋亡的机制提供了新的见解。所有导致藤黄酸诱导自噬和细胞凋亡的分子事件都是由活性氧介导的。一般意义：由于藤黄酸以各种细胞生存分子为靶标，因此它可能被认为是一种潜在的抗膀胱癌药物。(C)2014爱思唯尔B.V.保留所有权利。
Background: Gambogic acid is a potent anticancer agent and has been found effective against various types of cancer cells. The present study was addressed to explore the cytotoxic potential of Gambogic acid and the modulation of autophagy and apoptosis in bladder cancer cells T24 and UMUC3.Methods: Bladder cancer cell lines 124 and UMUC3 were treated with Gambogic acid, apoptosis was checked by flow-cytometry and expression of various autophagy and apoptosis related proteins was monitored by Western blotting. Confocal microscope was used for colocalization of p62 and Beclin-1.Results: Gambogic acid induces reactive oxygen species, and elicits a strong autophagic response by activating JNK at earlier time points, which is inhibited at later time points with the activation of caspases. Reactive oxygen species mediated caspase activation causes degradation of autophagic proteins, cleavage of molecular chaperones (Hsp90 and GRP-78) and adaptor proteins (p62 and NBR1). Gambogic acid treatment results in mitochondrial hyperpolarization and cytochrome c release and activates caspases involved in both extrinsic and intrinsic apoptotic pathways. Gambogic acid abrogates NF-kappa B activation by ROS mediated inhibition of I kappa B-alpha phosphorylation. Functionally Gambogic acid induced autophagy acts as a strong cell survival response and delays caspase activation.Conclusion: Our study provides the new insights about the mechanism of Gambogic acid induced modulation of autophagy and apoptosis in bladder cancer cells. All the molecular events responsible for Gambogic acid induced autophagy and apoptosis are mediated by reactive oxygen species.General significance: Since Gambogic acid targets various cell survival molecules therefore, it may be considered as a potential anticancer agent against bladder cancer. (C) 2014 Elsevier B.V. All rights reserved.