Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite the anticancer capabilities of emodin observed in many cancers, including EOC, the underlying molecular mechanism remains to be elucidated. A crucial link has been discovered between the acquisition of metastatic traits and the epithelial-mesenchymal transition (EMT). The present study aimed to determine whether emodin could inhibit the EMT of EOC cells and explore the underlying mechanism. The CCK-8 assay and transwell assay showed that emodin effectively repressed the abilities of proliferation, invasion, and migration in A2780 and SK-OV-3 cells. The Western blot showed that emodin upregulated epithelial markers (E-cadherin and Claudin) while it downregulated mesenchymal markers (N-cadherin and Vimentin) and transcription factor (Slug) in a dose-dependent fashion. After transfection of siRNA-Slug, both Slug and N-cadherin were downregulated in EOC cells while E-cadherin was upregulated, which was intensified by emodin. Besides, emodin decreased the expression of ILK, p-GSK-3β, β-catenin, and Slug. Transfection of siRNA-ILK also achieved the same effects, which was further strengthened by following emodin treatment. Nevertheless, SB216763, an inhibitor of GSK-3β, could reverse the effects of emodin except for ILK expression. These findings suggest that emodin inhibited the EMT of EOC cells via ILK/GSK-3β/Slug signaling pathway.

Emodin suppresses proliferation, migration and invasion in ovarian cancer cells by down regulating ILK in vitro and in vivo

“… 38 Further, in a previous study, carried out in our own laboratory, it was speculated that emodin inhibits EMT via the ILK/GSK3β/Slug signaling pathway in vitro. 28 In our current study, it was also found that emodin decreased the expression of ILK, resulting in a repression of the abilities of EOC cells to migrate and invade through restraining EMT. Further, the effect of the overexpression of ILK could be reduced by emodin treatment in vitro.…”

“… 25 – 27 Furthermore, our previous studies have demonstrated that emodin inhibits the EMT of EOC cells via the ILK/GSK3β/Slug signaling pathway in vitro. 28 …”

<p>Emodin Reverses the Epithelial–Mesenchymal Transition of Human Endometrial Stromal Cells by Inhibiting ILK/GSK-3β Pathway</p>

“… 40 , 41 Lu et al demonstrated that emodin decreased the invasion and metastasis abilities of epithelial ovarian cancer cells by inhibiting the EMT via ILK/GSK-3β/Slug signaling pathway. 42 Consistent with this, our study demonstrated that GSK-3β down-regulated the expression of β-catenin and slug and played essential roles in reversing the EMT procedure through which emodin inhibited the migration and invasion abilities of endometrial stromal cells. Thus, we supposed that emodin inhibited the migration and invasion abilities of EESs by reversing the EMT of endometrial stromal cells through ILK/GSK-3β/β-catenin/slug pathway.…”

EMT: Present and future in clinical oncology

“…An example is the inhibition of ILK, an integrin‐linked kinase involved in AKT pathway activation leading to EMT (Jiang et al ., ). Treatment with emodin (1,3,8‐trihydroxy‐6‐methylanthraquinone) (Bruney et al ., ), promotes a MET process by targeting ILK in ovarian cancer (Lu et al ., ) and endometrial sarcoma cells (Zheng et al ., ), in addition to reducing EMT through the ILK/AKT/mTOR signaling pathway in breast cancer cells (Ma et al ., ) (Fig. ).…”