Silibinin-induced apoptosis of breast cancer cells involves mitochondrial impairment
Silibinin-induced apoptosis of breast cancer cells involves mitochondrial impairment
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水飞蓟宾诱导的乳腺癌细胞凋亡涉及线粒体损伤
DOI：
10.1016/j.abb.2019.05.009
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发表时间：
2019-08-15
影响因子：
3.9
通讯作者：
Ikejima, Takashi
中科院分区：
文献类型：
--
作者：
Si, Lingling;Liu, Weiwei;Ikejima, Takashi
线粒体受分裂和融合过程的动态调节。水飞蓟宾诱导MCF-7和MDA-MB-231人乳腺癌细胞凋亡然而，线粒体功能障碍是否参与了水飞蓟宾诱导的两种类型的细胞凋亡仍不清楚。我们在这里报告，水飞蓟宾减少线粒体质量方面的MitoTracker绿色染色在两个乳腺癌细胞。水飞蓟宾诱导线粒体形态发生相应的改变，由椭圆形变为截短或碎片状。透射电子显微镜观察到线粒体中有浓缩的峰。水飞蓟宾引起线粒体膜电位降低。包括动力蛋白相关蛋白1（DRP 1）在内的线粒体分裂相关蛋白的表达上调，而线粒体融合相关蛋白视神经萎缩1（optic atrophy 1）和线粒体融合蛋白1（mitofusin 1）的表达下调。此外，水飞蓟宾治疗下调ATP含量以及线粒体生物发生调节剂的水平，包括线粒体转录因子A、过氧化物酶体增殖物激活受体γ共激活因子1和核呼吸因子2。此外，DRP 1抑制剂，mdivi-1，或DRP 1靶向siRNA的治疗有效地防止水飞蓟宾诱导的乳腺癌细胞凋亡，而抑制DRP 1磷酸化与星形孢菌素增加凋亡。综上所述，我们得出结论，水飞蓟宾损害线粒体动力学和生物合成，导致MCF-7和MDA-MB-123细胞凋亡。
Mitochondria are dynamically regulated by fission and fusion processes. Silibinin induces apoptosis of MCF-7 and MDA-MB-231 human breast cancer cells. However, whether or not mitochondria dysfunction is involved in the apoptosis induction with silibinin of both types of the cells remains unknown. We here report that silibinin decreases the mitochondrial mass in terms of MitoTracker Green staining in both breast cancer cells. Silibinin induces morphological changes of mitochondria from oval to truncated or fragmented shapes accordingly. Condensed crests are observed in mitochondria by transmission electron microscopy. Silibinin causes mitochondrial membrane potential reduced. The expression of mitochondrial fission-associated proteins including dynamin-related protein 1 (DRP1) is up-regulated, whereas expression of the mitochondrial fusion-associated proteins, optic atrophy 1 and mitofusin 1, is down-regulated. In addition, silibinin treatment down-regulates ATP content as well as the levels of mitochondrial biogenesis-regulators including mitochondrial transcription factor A, peroxisome proliferator-activated receptor gamma coactivator 1 and nuclear respiratory factor 2. Moreover, treatments with DRP1 inhibitor, mdivi-1, or with DRP1-targetted siRNA efficiently prevent silibinin-induced apoptosis in the breast cancer cells, whereas inhibition of DRP1 phosphorylation with staurosporine increases apoptosis furthermore. Taken together, we conclude that silibinin impairs mitochondrial dynamics and biogenesis, leading to apoptosis of MCF-7 and MDA-MB-123 cells.