Silibinin induces mitochondrial NOX4-mediated endoplasmic reticulum stress response and its subsequent apoptosis.
Silibinin induces mitochondrial NOX4-mediated endoplasmic reticulum stress response and its subsequent apoptosis.
复制标题
硅蛋白诱导线粒体NOX4介导的内质网应激反应及其随后的凋亡。
DOI：
10.1186/s12885-016-2516-6
复制
发表时间：
2016-07-12
期刊：
影响因子：
3.8
通讯作者：
Ahn SC
中科院分区：
文献类型：
--
作者：
Kim SH;Kim KY;Yu SN;Seo YK;Chun SS;Yu HS;Ahn SC
水飞蓟宾是一种具有生物活性的化合物，对肿瘤细胞具有化学预防作用。最近有报道，水飞蓟宾通过激活凋亡信号通路抑制肿瘤生长。尽管有多种证据表明水飞蓟宾参与了多种信号通路的凋亡，但目前还没有研究表明ROS介导的前列腺癌PC-3细胞凋亡的机制。一些研究表明活性氧（ROS）在各种信号级联中起重要作用，但ROS的主要来源目前尚不清楚。MTT法检测水飞蓟宾对前列腺细胞株生长的影响。我们使用流式细胞术检测水飞蓟宾是否通过产生ROS诱导细胞凋亡。Western blotting和RT-PCR检测细胞凋亡相关蛋白和内质网相关基因的表达。结果表明，水飞蓟宾通过NOX 4表达触发线粒体ROS产生，最终导致诱导凋亡。此外，线粒体ROS通过破坏Ca 2+稳态引起ER应激。ROS抑制剂的共同处理通过抑制NOX 4的表达来减少水飞蓟宾诱导的细胞凋亡，导致Ca 2+水平和ER应激反应的降低。总之，水飞蓟宾通过NOX 4诱导线粒体ROS依赖性凋亡，NOX 4与Ca 2+稳态和ER应激反应的破坏有关。因此，调节线粒体ROS产生者NOX 4可能是治疗前列腺癌的潜在靶点。本文的在线版本（doi：10.1186/s12885-016-2516-6）包含补充材料，可供授权用户使用。
Silibinin, a biologically active compound of milk thistle, has chemopreventive effects on cancer cell lines. Recently it was reported that silibinin inhibited tumor growth through activation of the apoptotic signaling pathway. Although various evidences showed multiple signaling pathways of silibinin in apoptosis, there were no reports to address the clear mechanism of ROS-mediated pathway in prostate cancer PC-3 cells. Several studies suggested that reactive oxygen species (ROS) play an important role in various signaling cascades, but the primary source of ROS was currently unclear. The effect of silibinin was investigated on cell growth of prostate cell lines by MTT assay. We examined whether silibinin induced apoptosis through production of ROS using flow cytometry. Expression of apoptosis-, endoplasmic reticulum (ER)-related protein and gene were determined by western blotting and RT-PCR, respectively. Results showed that silibinin triggered mitochondrial ROS production through NOX4 expression and finally led to induce apoptosis. In addition, mitochondrial ROS caused ER stress through disruption of Ca2+ homeostasis. Co-treatment of ROS inhibitor reduced the silibinin-induced apoptosis through the inhibition of NOX4 expression, resulting in reduction of both Ca2+ level and ER stress response. Taken together, silibinin induced mitochondrial ROS-dependent apoptosis through NOX4, which is associated with disruption of Ca2+ homeostasis and ER stress response. Therefore, the regulation of NOX4, mitochondrial ROS producer, could be a potential target for the treatment of prostate cancer. The online version of this article (doi:10.1186/s12885-016-2516-6) contains supplementary material, which is available to authorized users.