Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion
Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion
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水飞蓟宾通过诱导线粒体融合抑制乳腺癌MDA-MB-231细胞的迁移和侵袭
DOI：
10.1007/s11010-019-03640-6
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发表时间：
2019-10-14
影响因子：
4.3
通讯作者：
Ikejima, Takashi
中科院分区：
文献类型：
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作者：
Si, Lingling;Fu, Jianing;Ikejima, Takashi
人三阴性乳腺癌细胞MDA-MB-231显示出与癌症进展相关的典型上皮向间充质转化。线粒体在癌症进展（包括转移）中发挥着重要作用。线粒体结构的变化影响细胞迁移、自噬和凋亡。水飞蓟宾有抗乳腺癌作用。我们在这里报告，水飞蓟宾在较低浓度（30-90 μ M）抑制MDA-MB-231的上皮间质转化（EMT），通过增加上皮标记，E-钙粘蛋白的表达，并减少间质标记，N-钙粘蛋白和波形蛋白的表达。此外，水飞蓟宾对细胞迁移的抑制与基质金属蛋白酶2和9（MMP 2和MMP 9）以及桩蛋白的蛋白表达的减少有关。此外，水飞蓟宾处理通过下调线粒体分裂相关蛋白动力蛋白相关蛋白1（DRP 1）的表达和上调线粒体融合相关蛋白、视神经萎缩1、线粒体融合蛋白1和线粒体融合蛋白2的表达来增加线粒体融合。水飞蓟宾通过下调线粒体生物合成调节因子包括线粒体转录因子A（TFAM）、过氧化物酶体增殖物激活受体γ共激活因子（PGC 1）和核呼吸因子（NRF 2）的水平来干扰线粒体生物合成。此外，DRP 1和水飞蓟宾抑制细胞迁移，而MFN 1和MFN 2抑制细胞迁移，线粒体融合参与水飞蓟宾对细胞迁移的负作用。水飞蓟宾减少活性氧（ROS）的产生，导致抑制NLRP 3炎性小体激活。此外，敲低丝裂融合蛋白1和2（MFN 1和2）减轻了水飞蓟宾诱导的NLRP 3炎性体活化的抑制。ROS的抑制有助于抑制NLRP 3、半胱天冬酶-1和IL-β蛋白的表达以及细胞迁移。总之，我们的研究提供了证据表明，水飞蓟宾损害线粒体动力学和生物发生，导致MDA-MB-231乳腺癌细胞的迁移和侵袭减少。
Human triple negative breast cancer cells, MDA-MB-231, show typical epithelial to mesenchymal transition associated with cancer progression. Mitochondria play a major role in cancer progression, including metastasis. Changes in mitochondrial architecture affect cellular migration, autophagy and apoptosis. Silibinin is reported to have anti-breast cancer effect. We here report that silibinin at lower concentrations (30-90 mu M) inhibits epithelial to mesenchymal transition (EMT) of MDA-MB-231, by increasing the expression of epithelial marker, E-cadherin, and decreasing the expression of mesenchymal markers, N-cadherin and vimentin. Besides, silibinin inhibition of cell migration is associated with reduction in the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) and paxillin. In addition, silibinin treatment increases mitochondrial fusion through down-regulating the expression of mitochondrial fission-associated protein dynamin-related protein 1 (DRP1) and up-regulating the expression of mitochondrial fusion-associated proteins, optic atrophy 1, mitofusin 1 and mitofusin 2. Silibinin perturbed mitochondrial biogenesis via down-regulating the levels of mitochondrial biogenesis regulators including mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor gamma coactivator (PGC1) and nuclear respiratory factor (NRF2). Moreover, DRP1 knockdown or silibinin inhibited cell migration, and MFN1&2 knockdown restored it. Mitochondrial fusion contributes to silibinin's negative effect on cell migration. Silibinin decreased reactive oxygen species (ROS) generation, leading to inhibition of the NLRP3 inflammasome activation. In addition, knockdown of mitofusin 1&2 (MFN 1&2) relieved silibinin-induced inhibition of NLRP3 inflammasome activation. Repression of ROS contributes to the inhibition of the expression of NLRP3, caspase-1 and IL-beta proteins as well as of cell migration. Taken together, our study provides evidence that silibinin impairs mitochondrial dynamics and biogenesis, resulting in reduced migration and invasion of the MDA-MB-231 breast cancer cells.