Cyanidin-3-o-Glucoside Pharmacologically Inhibits Tumorigenesis via Estrogen Receptor β in Melanoma Mice.

Mei Liu,Lijun Zhou,Hanlu Fan,Haiwen Li,Li Wang,Yaqi Du,Donata Ponikwicka-Tyszko,Mingming Wang,Agata Pilaszewicz-Puza,Slawomir Wolczynnski,Yang-Dong Guo,Weronika Lebiedzinska,Huijiao Liu,Xiangdong Li,Nafis Rahman,Hua You

doi:10.3389/fonc.2019.01110

Abstract

Expression patterns of estrogen receptors [ERα, ERβ, and G-protein associated ER (GPER)] in melanoma and skin may suggest their differential roles in carcinogenesis. Phytoestrogenic compound cyanidin-3-o-glucoside (C3G) has been shown to inhibit the growth and metastatic potential of melanoma, although the underlying molecular mechanism remains unclear. The aim of this study was to clarify the mechanism of action of C3G in melanoma in vitro and in vivo, as well as to characterize the functional expressions of ERs in melanoma. In normal skin or melanoma (n = 20/each), no ERα protein was detectable, whereas expression of ERβ was high in skin but weak focal or negative in melanoma; and finally high expression of GPER in all skin vs. 50% melanoma tissues (10/20) was found. These results correspond with our analysis of the melanoma survival rates (SRs) from Human Protein Atlas and The Cancer Genome Atlas GDC (362 patients), where low ERβ expression in melanoma correlate with a poor relapse-free survival, and no correlations were observed between SRs and ERα or GPER expression in melanoma. Furthermore, we demonstrated that C3G treatment arrested the cell cycle at the G2/M phase by targeting cyclin B1 (CCNB1) and promoted apoptosis via ERβ in both mouse and human melanoma cell lines, and inhibited melanoma cell growth in vivo. Our study suggested that C3G elicits an agonistic effect toward ERβ signaling enhancement, which may serve as a potential novel therapeutic and preventive approach for melanoma.

Highlights

Melanoma skin cancer with the rising incidence, originates from pigment-producing cells melanocytes, found in the basal layer of the epidermis and in the eye [1]
In order to validate the expressions of these three ERβEstrogen receptors (ERs) in the large numbers of the melanoma patients, we explored the expressions of ERα, ERβ, and G protein-coupled estrogen receptor (GPER) in The Cancer Genome Atlas (TCGA) GDC Melanoma with 352 human samples
A growing body of evidence shows the preventive roles for estrogen and its ERs signaling pathway in melanoma, and suggests that ERs may be the potential therapeutic targets associated with a suppressive function in them

Summary

Introduction

Melanoma skin cancer with the rising incidence, originates from pigment-producing cells melanocytes, found in the basal layer of the epidermis and in the eye [1]. Estrogen receptors (ERs), such as nuclear ERα and ERβ, and G protein-coupled estrogen receptor (GPER), are aberrantly expressed in a wide variety of malignancies other than estrogenrelated cancers, and ERβ expression has been reported to decline in tumor tissues compared with normal tissues [3,4,5,6]. Studies have shown that ERβ is the predominant ER subtype, while ERα is not detected in human melanoma cell lines [7] or melanocytic lesions [8, 9]. An activation of GPER signaling that inhibits melanoma has been reported in two melanoma cell lines [13], which may expand the understandings of the melanoma carcinogenesis

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