Tan Weiwei, Pan Meihong, Liu Hui, Tian Hequn, Ye Qing, Liu Hongda
Department of Traditional Chinese Medicine, Yidu Central Hospital of Weifang, Weifang, Shandong, China.
Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China.
Onco Targets Ther. 2017 Jul 13;10:3467-3474. doi: 10.2147/OTT.S139009. eCollection 2017.
Ergosterol peroxide (EP), a sterol derived from medicinal mushrooms, has been reported to exert antitumor activity in several tumor types. However, the role of EP toward ovarian cancer cells has not been investigated. In this study, we analyzed the cytotoxicity of EP in various cell lines representing high-grade serous ovarian cancer and low-grade serous ovarian cancer, respectively. Although EP showed no significant inhibition of the viability of normal ovarian surface epithelial cells, it impaired the proliferation and invasion capacities of tumor cells in a dose-dependent manner. We further figured out key modulators involved in its antitumor effects by quantitative reverse transcription polymerase chain reaction, ELISA, and Western blot. The nuclear β-catenin was down-regulated upon EP treatment, subsequently reducing the Cyclin D1 and c-Myc expression levels. Meanwhile, the protein level of protein tyrosine phosphatase SHP2 was up-regulated in EP treated cells, whereas Src kinase activity was inhibited. Both activation of SHP2 phosphatase and inhibition of Src kinase decreased the phosphorylation level of transducer and activator of STAT3 protein, which was implicated in oncogenesis. On the other hand, EP remarkably inhibited the expression and secretion of VEGF-C, implying its involvement in counteracting tumor angiogenesis. Moreover, EP treatment showed comparable cytotoxic effect with β-catenin knock-down or STAT3 inhibition. Taken together, our results demonstrated that EP showed antitumor effects toward ovarian cancer cells through both β-catenin and STAT3 signaling pathways, making it a promising candidate for drug development.
过氧化麦角甾醇（EP）是一种从药用蘑菇中提取的甾醇，据报道在多种肿瘤类型中具有抗肿瘤活性。然而，EP对卵巢癌细胞的作用尚未得到研究。在本研究中，我们分析了EP对分别代表高级别浆液性卵巢癌和低级别浆液性卵巢癌的各种细胞系的细胞毒性。尽管EP对正常卵巢表面上皮细胞的活力没有显著抑制作用，但它以剂量依赖的方式损害了肿瘤细胞的增殖和侵袭能力。我们通过定量逆转录聚合酶链反应、酶联免疫吸附测定和蛋白质免疫印迹进一步确定了参与其抗肿瘤作用的关键调节因子。EP处理后，核β-连环蛋白下调，随后降低了细胞周期蛋白D1和c-Myc的表达水平。同时，在EP处理的细胞中，蛋白酪氨酸磷酸酶SHP2的蛋白水平上调，而Src激酶活性受到抑制。SHP2磷酸酶的激活和Src激酶的抑制均降低了信号转导子和转录激活子3（STAT3）蛋白的磷酸化水平，STAT3与肿瘤发生有关。另一方面，EP显著抑制了血管内皮生长因子C（VEGF-C）的表达和分泌，这意味着它参与了对抗肿瘤血管生成的过程。此外，EP处理显示出与β-连环蛋白敲低或STAT3抑制相当的细胞毒性作用。综上所述，我们的结果表明，EP通过β-连环蛋白和STAT3信号通路对卵巢癌细胞显示出抗肿瘤作用，使其成为药物开发的一个有前景的候选物。
