Abstract
Traditional Chinese medicine has gained popularity due to its ability to kill tumor cells. Recently, the apoptotic and anti-angiogenic effects of Trametes robiniophila murr (Huaier) have been investigated. The aim of this study was to investigate its effect on cell mobility and tumor growth in ovarian cancer. Cell viability and motility were measured using SRB, scratch and migration assays. Cell apoptosis was analysed by annexin V/PI staining. Using a reverse-phase protein array (RPPA) assay, we analyzed the levels of 153 proteins and/or phosphorylations in Huaier-treated and untreated cells. Huaier inhibited cell viability and induced both early and late apoptosis in SKOV3, SKOV3.ip1 and Hey cells in a time- and dose-dependent manner. Cell invasiveness and migration were also suppressed significantly. The RPPA results showed significant differences (of at least 30%; P <0.05) in the levels of 7 molecules in SKOV3 cells and 10 in SKOV3.ip1 cells between the untreated and treated cells. Most of the molecules identified play roles in cell proliferation, apoptosis or cell adhesion/invasion. Western blot analysis further validated that Huaier treatment resulted in decreased AKT phosphorylation, enhanced expression of total GSK3β, inhibition of the phosphorylation of GSK3β on S9, reduction of both cytoplasmic β-catenin expression and nuclear β-catenin translocation, and transcriptional repression of several Wnt/β-catenin target genes (DIXDC1, LRP6, WNT5A, and cyclin D1). After knocking down GSK3β, β-catenin expression could not be inhibited by Huaier. Finally, Huaier inhibited the growth of ovarian tumor xenografts in vivo. These studies indicate that Huaier inhibits tumor cell mobility in ovarian cancer via the AKT/GSK3β/β-catenin signaling pathway.
Highlights
Epithelial ovarian cancer is a leading cause of death from gynecologic cancer in the United States and the fifth most common cause of cancer mortality in women[1]
After the cells were treated with Huaier for 24, 48, 72 and 96 hours at various concentrations (0, 0.625, 1.25, 2.5, 5 and 10 mg/ml), Huaier significantly inhibited the growth of the SKOV3, SKOV3.ip1 and Hey cells in a time- and dosedependent manner (Figure 1)
The Hey and SKOV3.ip1 cells were more sensitive to the Huaier treatment, as the viability rates were decreased to 31.94% (72 hours, p,0.001) and 20.43% (96 hours, p,0.001) in the SKOV3.ip1 cells, 4.9% (72 hours, p,0.001) and 3.1% (96 hours, p,0.001) in the Hey cells compared with 61.1% (72 hours, p = 0.01) and 40.1% (96 hours, p,0.001) in the SKOV3 cells
Summary
Epithelial ovarian cancer is a leading cause of death from gynecologic cancer in the United States and the fifth most common cause of cancer mortality in women[1]. The overall survival of advanced ovarian cancer has not proved promising, even after surgery combined with new adjuvant strategies, such as high dose chemotherapy with peripheral blood stem cell transplantation, dose-dense weekly paclitaxel with carboplatin, and targeted therapy with carboplatin/paclitaxel. Results from a randomized phase III trial (GOG 0208) showed that the use of bevacizumab (an Endothelial Growth Factor Receptor antibody) during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by approximately 4 months in patients with advanced epithelial ovarian cancer[2]. The overall survival is similar to conventional therapy despite the high expense. Because none of these strategies can completely protect ovarian cancer patients from recurrence and metastasis, new drugs are urgently needed
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