Resveratrol depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation.
Resveratrol depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation.
复制标题
DOI：
10.1016/j.mito.2012.10.010
复制
发表时间：
2013-09
期刊：
影响因子：
4.4
通讯作者：
Chandra, Dhyan
中科院分区：
文献类型：
--
作者：
Prabhu, Varun;Srivastava, Pragya;Yadav, Neelu;Amadori, Michael;Schneider, Andrea;Seshadri, Athul;Pitarresi, Jason;Scott, Rachael;Zhang, Honghao;Koochekpour, Shahriar;Gogada, Raghu;Chandra, Dhyan
我们最近证实，白藜芦醇可以诱导多种类型的癌细胞发生caspase依赖性的凋亡。细胞凋亡是否也受到自噬等其他细胞死亡机制的调控还没有明确的定义。在这里，我们表明，抑制自噬增强了白藜芦醇诱导的半胱氨酸天冬氨酸酶的激活和凋亡。白藜芦醇抑制多种癌细胞的集落形成和细胞增殖。白藜芦醇诱导自噬的关键标志--LC3-II的积聚。3-甲基腺嘌呤(3-MA)是一种自噬抑制剂，可增加白藜芦醇介导的caspase激活和乳腺和结肠癌细胞的死亡。通过沉默关键的自噬调节因子如ATG5和Beclin-1来抑制自噬增强了白藜芦醇诱导的caspase的激活。机制分析表明Beclin-1不与促凋亡蛋白Bax和Bak相互作用，但经白藜芦醇处理后，Beclin-1与胞浆和线粒体中的P53相互作用。重要的是，白藜芦醇耗尽了ATPase 8基因，从而减少了线粒体DNA(MtDNA)的含量，这表明白藜芦醇导致线粒体DNA损伤，导致功能障碍的线粒体积累，从而触发自噬诱导。总之，我们的发现表明，在白藜芦醇诱导的细胞凋亡过程中，自噬的诱导是一种适应性反应。
We recently demonstrated that resveratrol induces caspase-dependent apoptosis in multiple cancer cell types. Whether apoptosis is also regulated by other cell death mechanisms such as autophagy is not clearly defined. Here we show that inhibition of autophagy enhanced resveratrol-induced caspase activation and apoptosis. Resveratrol inhibited colony formation and cell proliferation in multiple cancer cell types. Resveratrol treatment induced accumulation of LC3-II, which is a key marker for autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased resveratrol-mediated caspase activation and cell death in breast and colon cancer cells. Inhibition of autophagy by silencing key autophagy regulators such as ATG5 and Beclin-1 enhanced resveratrol-induced caspase activation. Mechanistic analysis revealed that Beclin-1 did not interact with proapoptotic proteins Bax and Bak; however, Beclin-1 was found to interact with p53 in the cytosol and mitochondria upon resveratrol treatment. Importantly, resveratrol depleted ATPase 8 gene, and thus, reduced mitochondrial DNA (mtDNA) content, suggesting that resveratrol induces damage to mtDNA causing accumulation of dysfunctional mitochondria triggering autophagy induction. Together, our findings indicate that induction of autophagy during resveratrol-induced apoptosis is an adaptive response.
登录
查看更多内容
影响因子：
4.8
作者：
Gogada, Raghu;Prabhu, Varun;Chandra, Dhyan
通讯作者：
Chandra, Dhyan
影响因子：
7
作者：
Heid, CA;Stevens, J;Williams, PM
通讯作者：
Williams, PM
DNA超螺旋抑制了实时PCR：一种定量线粒体DNA损伤和修复的新方法。
影响因子：
14.9
作者：
Chen J;Kadlubar FF;Chen JZ
通讯作者：
Chen JZ
影响因子：
3.9
作者：
Chung, Sangwoon;Yao, Hongwei;Caito, Samuel;Hwang, Jae-Woong;Arunachalam, Gnanapragasam;Rahman, Irfan
通讯作者：
Rahman, Irfan
DOI：
10.18632/aging.100056
发表时间：
2009-06-03
期刊：
Aging
影响因子：
--
作者：
Armour SM;Baur JA;Hsieh SN;Land-Bracha A;Thomas SM;Sinclair DA
通讯作者：
Sinclair DA