Abstract
BackgroundOvarian cancer is the most lethal gynaecological malignancy. Chemotherapy is the main stay of treatment for metastatic disease, with modest response rates but significant side effects. Therefore, there is a need for alternative therapies that can control the disease while offering good quality of life. Ovarian cancer cells express both estrogen receptor subtypes (ERα and ERβ). There is growing evidence that ERβ is anti-oncogenic. Genistein and daidzein are phytoestrogens found in soybeans and they display higher affinity to bind ERβ. ERB-041 is a potent selective ERβ agonist. In this study, we aimed to investigate the effects of genistein, daidzein and ERB-041 on ovarian cancer.MethodsOvarian cancer cell lines were treated with genistein, daidzein and ERB-041 in pharmacological doses. Cell migration, invasion, proliferation, cell cycle arrest, apoptosis and sphere formation were assessed by Transwell migration and invasion assays, XTT assay, focus formation, flow cytometry and sphere formation assay, respectively. Immunoblotting analysis was performed to determine the downstream signaling pathways.ResultsWe found that genistein, daidzein and ERB-041 significantly inhibited ovarian cancer cell migration, invasion, proliferation, as well as induced cell cycle arrest and apoptosis. Significantly inhibitory effect on the size and number of sphere formed in genistein, daidzein and ERB-041 treated cells was also demonstrated. Moreover, genistein, daidzein and ERB-041 treatment reduced p-FAK, p-PI3K, p-AKT, p-GSK3β, p21 or cyclin D1 expression in ovarian cancer cells.ConclusionGenistein, daidzein and ERB-041 decreased ovarian cancer cell migration, invasion, proliferation and sphere formation, and induced cell cycle arrest and apoptosis with altered FAK and PI3K/AKT/GSK signaling and p21/cyclin D1 expression, suggesting their roles on ovarian cancer cell metastasis, tumorigenesis and stem-like properties and their potential as alternative therapies for ovarian cancer patients.
Highlights
Ovarian cancer is the most lethal gynaecological malignancy
Knockdown of ERβ increased ovarian cancer cell migration and invasion We showed the inhibitory effect of genistein, daidzein and ERB-041 on ovarian cancer cell migration and invasion
Daidzein and ERB-041 inhibited cell proliferation in a dose- and time-dependent manner (Fig. 5a–c)
Summary
Ovarian cancer is the most lethal gynaecological malignancy. Chemotherapy is the main stay of treat‐ ment for metastatic disease, with modest response rates but significant side effects. Ovarian cancer cells express both estrogen receptor subtypes (ERα and ERβ). Soy isoflavones are non-steroidal compounds found in plants, with similar chemical structure to 17-β-estradiol [8, 9] and considered as phytoestrogens They can mimic the binding of estrogens to ERs, exerting estrogenic effects on target organs [8, 9]. Genistein and daidzein are two major isoflavones, constituting 60 and 30% of total isoflavones respectively found in soybeans [9] They have higher affinities for ERβ than ERα [11, 12]. Genistein has been reported to inhibit cell proliferation, induce apoptosis, regulate cell cycle, modulate antioxidant effect and impair angiogenesis in both hormone-related and -unrelated cancer cells, including ovarian cancer [13]. Daidzein has been shown to inhibit cell proliferation, affect cell cycle and angiogenesis in different types of cancer cells [8], whereas studies on daidzein on ovarian cancer were scanty, and the underlying mechanisms were still poorly defined
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