Our previous studies showed that silibinin promoted activation of caspases to induce apoptosis in human breast cancer MCF-7 cells by down-regulating the protein expression level of estrogen receptor (ER) α and up-regulating ERβ. Recently, it has been reported that silibinin-induced apoptosis also involved nuclear translocation of apoptosis-inducing factor (AIF). Here we report that silibinin induces nuclear translocation of AIF through the down-regulation of ERα and up-regulation of ERβ in a concentration dependent manner in MCF-7 cells. AIF knockdown with siRNA significantly reverses silibinin-induced apoptosis. The nuclear translocation of AIF is enhanced by treatment with MPP, an ERα antagonist, and blocked with PPT, an ERα agonist. In contrast to ERα activity, the nuclear AIF is increased with an ERβ agonist, DPN and blocked with an ERβ antagonist, PHTPP. Autophagy, negatively regulated by ERα, positively controls AIF-mediated apoptosis, as evidenced by the preventive effect of autophagy inhibitor 3-MA and siRNA targeting LC3, on the nuclear translocation of AIF and cell death induced by silibinin co-treatment with or without MPP. In sum we conclude that AIF in nuclei is involved in silibinin-induced apoptosis, and the nuclear translocation of AIF is increased by down-regulated ERα pathway and/or up-regulated ERβ pathway in MCF-7 cells, accompanying up-regulation of autophagy.

我们之前的研究表明，水飞蓟宾通过下调雌激素受体 (ER) α 的蛋白表达水平和上调 ERβ 来促进 caspase 的活化，从而诱导人乳腺癌 MCF-7 细胞凋亡。最近，有报道称水飞蓟宾诱导的细胞凋亡也涉及细胞凋亡诱导因子（AIF）的核转位。在这里，我们报告水飞蓟宾在 MCF-7 细胞中以浓度依赖性方式通过下调 ERα 和上调 ERβ 诱导 AIF 的核易位。用 siRNA 敲低 AIF 可显着逆转水飞蓟宾诱导的细胞凋亡。AIF 的核转位通过用 MPP（一种 ERα 拮抗剂）处理得到增强，并用 PPT（一种 ERα 激动剂）阻断。与 ERα 活性相反，核 AIF 会随着 ERβ 激动剂而增加，DPN 并被 ERβ 拮抗剂 PHTPP 阻断。自噬，由 ERα 负调控，正控制 AIF 介导的细胞凋亡，如自噬抑制剂 3-MA 和靶向 LC3 的 siRNA 对 AIF 核易位和由水飞蓟宾联合或不使用 MPP 诱导的细胞死亡的预防作用所证明. 总之，我们得出结论，细胞核中的 AIF 参与了水飞蓟宾诱导的细胞凋亡，并且 AIF 的核转位通过下调 MCF-7 细胞中的 ERα 通路和/或上调 ERβ 通路，伴随自噬的上调而增加。 . 关于 AIF 的核易位和由水飞蓟宾与 MPP 共同处理诱导的细胞死亡。总之，我们得出结论，细胞核中的 AIF 参与了水飞蓟宾诱导的细胞凋亡，并且 AIF 的核转位通过下调 MCF-7 细胞中的 ERα 通路和/或上调 ERβ 通路，伴随自噬的上调而增加。 . 关于 AIF 的核易位和由水飞蓟宾与 MPP 共同处理诱导的细胞死亡。总之，我们得出结论，细胞核中的 AIF 参与了水飞蓟宾诱导的细胞凋亡，并且 AIF 的核转位通过下调 MCF-7 细胞中的 ERα 通路和/或上调 ERβ 通路，伴随自噬的上调而增加。 .