Inhibition of mitochondria- and endoplasmic reticulum stress-mediated autophagy augments temozolomide-induced apoptosis in glioma cells.
Inhibition of mitochondria- and endoplasmic reticulum stress-mediated autophagy augments temozolomide-induced apoptosis in glioma cells.
复制标题
DOI：
10.1371/journal.pone.0038706
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shih CM
中科院分区：
文献类型：
--
作者：
Lin CJ;Lee CC;Shih YL;Lin CH;Wang SH;Chen TH;Shih CM
自噬是细胞通过降解细胞蛋白质和细胞器（包括线粒体和内质网（ER））来维持稳态和存活的重要过程。我们以前证明，替莫唑胺（TMZ），烷化剂脑肿瘤化疗，诱导活性氧（ROS）/细胞外信号调节激酶（ERK）介导的自噬，以保护胶质瘤细胞凋亡。在这项研究中，我们研究了线粒体损伤和ER应激在TMZ诱导的细胞毒性中的作用。线粒体去极化和线粒体通透性转换孔（MPTP）开放被观察到作为TMZ诱导的自噬的前奏，这些随后是线粒体质量的损失。电子传递链（ETC）抑制剂，如鱼藤酮（复合物I抑制剂），叠氮化钠（复合物IV抑制剂）和寡霉素（复合物V抑制剂），或MPTP抑制剂，环孢素A，减少线粒体损伤介导的自噬，因此增加TMZ诱导的细胞凋亡。TMZ处理引发ER应激，GADD 153和GRP 78蛋白表达增加，caspase 12蛋白表达减少。ER应激通过c-Jun N-末端激酶（JNK）和Ca 2+信号通路诱导自噬。TMZ与ER应激抑制剂4-苯基丁酸（4-PBA）的组合通过抑制自噬增强TMZ诱导的细胞毒性。总之，我们的数据表明TMZ通过线粒体损伤和ER应激依赖机制诱导自噬以保护胶质瘤细胞。这项研究提供的证据表明，针对线粒体或ER的药物可能是潜在的抗癌策略。
Autophagy is a crucial process for cells to maintain homeostasis and survival through degradation of cellular proteins and organelles, including mitochondria and endoplasmic reticula (ER). We previously demonstrated that temozolomide (TMZ), an alkylating agent for brain tumor chemotherapy, induced reactive oxygen species (ROS)/extracellular signal-regulated kinase (ERK)-mediated autophagy to protect glioma cells from apoptosis. In this study, we investigated the role of mitochondrial damage and ER stress in TMZ-induced cytotoxicity. Mitochondrial depolarization and mitochondrial permeability transition pore (MPTP) opening were observed as a prelude to TMZ-induced autophagy, and these were followed by the loss of mitochondrial mass. Electron transport chain (ETC) inhibitors, such as rotenone (a complex I inhibitor), sodium azide (a complex IV inhibitor), and oligomycin (a complex V inhibitor), or the MPTP inhibitor, cyclosporine A, decreased mitochondrial damage-mediated autophagy, and therefore increased TMZ-induced apoptosis. TMZ treatment triggered ER stress with increased expression of GADD153 and GRP78 proteins, and deceased pro-caspase 12 protein. ER stress consequently induced autophagy through c-Jun N-terminal kinases (JNK) and Ca2+ signaling pathways. Combination of TMZ with 4-phenylbutyrate (4-PBA), an ER stress inhibitor, augmented TMZ-induced cytotoxicity by inhibiting autophagy. Taken together, our data indicate that TMZ induced autophagy through mitochondrial damage- and ER stress-dependent mechanisms to protect glioma cells. This study provides evidence that agents targeting mitochondria or ER may be potential anticancer strategies.
登录
查看更多内容
DOI：
10.1016/j.bbrc.2010.07.050
发表时间：
2010-08-13
影响因子：
3.1
作者：
Hwang, Mi-Sun;Baek, Won-Ki
通讯作者：
Baek, Won-Ki
DOI：
10.1124/jpet.108.144113
发表时间：
2009-04-01
影响因子：
3.5
作者：
Oh, Seon-Hee;Lim, Sung-Chul
通讯作者：
Lim, Sung-Chul
影响因子：
9.7
作者：
Chen, Thomas C.;Wang, Weijun;Schoenthal, Axel H.
通讯作者：
Schoenthal, Axel H.
影响因子：
7.4
作者：
Lin, Chien-Ju;Lee, Chin-Cheng;Shih, Chwen-Ming
通讯作者：
Shih, Chwen-Ming
影响因子：
8
作者：
Isakovic, A.;Harhaji, L.;Trajkovic, V.
通讯作者：
Trajkovic, V.