Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China; Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1, Nakanomachi, Hachioji, Tokyo, 192-0015, Japan.
Arch Biochem Biophys. 2020 May 30;685:108284. doi: 10.1016/j.abb.2020.108284. Epub 2020 Jan 31.
We reported previously that higher doses (150-250 μM) of silibinin enhanced fission and inhibited fusion of mitochondria, accompanying apoptosis of double-positive breast cancer cell line MCF-7 cells and triple-negative breast cancer cell line MDA-MB-231 cells. We report here three important questions yet unclarified in the previous study; 1) Whether enhanced fission of mitochondria by the treatment of silibinin leads to mitophagy, 2) Whether mitophagy positively contributes to apoptosis and 3) Whether estrogen receptor-positive (ER) MCF-7 cells and estrogen receptor-negative (ER) MDA-MB-231 cells are affected in a different way by silibinin treatment, since silibinin often works through ERs signaling pathway. Mitophagy driven by Pink1/Parkin signaling, plays an important role in eliminating damaged mitochondria. Indeed, increased expression of Pink1 and the recruitment of Parkin and LC3-II to mitochondria by the treatment with silibinin account for silibinin induction of mitophagy. In this study, the effects of mitochondrial division inhibitor 1 (mdivi-1) and small interfering RNA targeting dynamin-related protein 1 (DRP1) were examined to reveal the effect of mitochondrial fission on mitophagy. As expected, mdivi-1 or siRNA targeting DRP1 reversed silibinin-induced mitochondrial fission due to down-regulation in the expression of DRP1. Inhibition of mitochondrial fission by mdivi-1 prevented induction of mitophagy as well as autophagy in both MCF-7 and MDA-MB-231 cells, indicating that silibinin-induced mitochondrial fission leads to mitophagy. Inhibition of mitochondrial fission efficiently prevented silibinin-induced apoptosis in MCF-7 and MDA-MB-231 cells in our previous work, and the second point of the present study, inhibition of mitophagy by Pink1 or Parkin knockdown increased silibinin-induced apoptosis of these cells, respectively, suggesting that the mitophagy induced by silibinin treatment serves as a cytoprotective effect, resulting in reduction of apoptosis of cancer cells in both cells. In the third point, we studied whether estrogen receptors (ERs) played a role in silibinin-induced mitophagy and apoptosis in MCF-7 and MDA-MB-231 cells. ERα and ERβ are not involved in silibinin-induced mitophagic process in MCF-7 and MDA-MB-231 cells. These findings demonstrated that silibinin induced mitochondria fission leads to mitophagy, which attenuates silibinin-induced apoptosis not through ERs-Pink1 or -Parkin pathway in MCF-7 and MDA-MB-231.
我们之前报道过，较高剂量（150-250μM）的水飞蓟宾增强了线粒体的裂变，抑制了融合，伴随着双阳性乳腺癌 MCF-7 细胞系和三阴性乳腺癌 MDA-MB-231 细胞系的细胞凋亡。我们在这里报告了之前研究中尚未阐明的三个重要问题；1）水飞蓟宾处理是否增强了线粒体的裂变导致自噬，2）自噬是否对凋亡有积极贡献，3）雌激素受体阳性（ER）的 MCF-7 细胞和雌激素受体阴性（ER）的 MDA-MB-231 细胞是否受到水飞蓟宾处理的不同影响，因为水飞蓟宾通常通过 ERs 信号通路起作用。由 Pink1/Parkin 信号驱动的线粒体自噬在消除受损线粒体方面起着重要作用。事实上，用水飞蓟宾处理后 Pink1 的表达增加，以及 Parkin 和 LC3-II 募集到线粒体，都说明了水飞蓟宾诱导了线粒体自噬。在这项研究中，检查了线粒体分裂抑制剂 1（mdivi-1）和靶向动力相关蛋白 1（DRP1）的小干扰 RNA 的作用，以揭示线粒体分裂对自噬的影响。正如预期的那样，mdivi-1 或靶向 DRP1 的 siRNA 由于 DRP1 表达下调而逆转了水飞蓟宾诱导的线粒体裂变。mdivi-1 抑制线粒体裂变防止了 MCF-7 和 MDA-MB-231 细胞中的自噬和线粒体自噬的诱导，表明水飞蓟宾诱导的线粒体裂变导致了线粒体自噬。在我们之前的工作中，抑制线粒体裂变有效地阻止了 MCF-7 和 MDA-MB-231 细胞中水飞蓟宾诱导的细胞凋亡，而本研究的第二点是，Pink1 或 Parkin 敲低抑制自噬会增加这些细胞中水飞蓟宾诱导的细胞凋亡，表明水飞蓟宾处理诱导的自噬作为一种细胞保护作用，导致两种细胞中癌细胞凋亡的减少。在第三点中，我们研究了雌激素受体（ERs）在 MCF-7 和 MDA-MB-231 细胞中水飞蓟宾诱导的线粒体自噬和细胞凋亡中的作用。在 MCF-7 和 MDA-MB-231 细胞中，ERα 和 ERβ 不参与水飞蓟宾诱导的线粒体自噬过程。这些发现表明，水飞蓟宾诱导的线粒体裂变导致了线粒体自噬，这减轻了水飞蓟宾诱导的凋亡，而不是通过 MCF-7 和 MDA-MB-231 中的 ERs-Pink1 或 -Parkin 途径。
Arch Biochem Biophys. 2019-5-11
Chin Med. 2025-6-9
Front Immunol. 2025-4-3
Cell Death Discov. 2024-10-29
Anticancer Agents Med Chem. 2024
Front Mol Biosci. 2022-9-23
World J Surg Oncol. 2022-10-3
Zotero 插件