Tumorigenic effects of endocrine-disrupting chemicals are alleviated by licorice (Glycyrrhiza glabra) root extract through suppression of AhR expression in mammalian cells.

Xiao Ting Chu,Seong Gu Hwang,Joseph De La Cruz,Heeok Hong

doi:10.7314/apjcp.2014.15.12.4809

Abstract

Endocrine-disrupting chemicals (EDCs) have been reported to interfere with estrogen signaling. Exposure to these chemicals decreases the immune response and causes a wide range of diseases in animals and humans. Recently, many studies showed that licorice (Glycyrrhiza glabra) root extract (LRE) commonly called "gamcho" in Korea exhibits antioxidative, chemoprotective, and detoxifying properties. This study aimed to investigate the mechanism of action of LRE and to determine if and how LRE can alleviate the toxicity of EDCs. LRE was prepared by vacuum evaporation and freeze-drying after homogenization of licorice root powder that was soaked in 80% ethanol for 72 h. We used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a representative EDC, which is known to induce tumors or cancers; MCF-7 breast cancer cells, used as a tumor model, were treated with TCDD and various concentrations of LRE (0, 50, 100, 200, 400 μg/mL) for 24, 48, and 72 h. As a result, TCDD stimulated MCF-7 cell proliferation, but LRE significantly inhibited TCDD-induced MCF-7 cell proliferation in a dose- and time-dependent manner. The expression of TCDD toxicity-related genes, i.e., aryl hydrocarbon receptor (AhR), AhR nuclear translocator, and cytochrome P450 1A1, was also down-regulated by LRE in a dose-dependent manner. Analysis of cell cycle distribution after treatment of MCF-7 cells with TCDD showed that LRE inhibited the proliferation of MCF-7 cells via G2/M phase arrest. Reverse transcription-polymerase chain reaction and Western blot analysis also revealed that LRE dose-dependently increased the expression of the tumor suppressor genes p53 and p27 and down-regulated the expression of cell cycle-related genes. These data suggest that LRE can mitigate the tumorigenic effects of TCDD in breast cancer cells by suppression of AhR expression and cell cycle arrest. Thus, LRE can be used as a potential toxicity-alleviating agent against EDC-mediated diseases.

Highlights

Endocrine-disrupting chemicals (EDCs) are natural or industrial compounds found in food and the environment that are capable of mimicking some of the effects of endogenous estrogens or interfering with estrogen signaling pathways by interacting with two estrogen receptors (ERs): ERα and ERβ (Pelekanou and Leclercq, 2011; Kerdivel et al, 2013)
This study investigated the antiproliferative activity of licorice (Glycyrrhiza glabra) root extract (LRE) in TCDD-stimulated MCF-7 human breast cancer cells
LRE mitigated the tumorigenic effects of TCDD in MCF-7 cells by suppressing aryl hydrocarbon receptor (AhR) expression and cell cycle arrest

Summary

Introduction

Endocrine-disrupting chemicals (EDCs) are natural or industrial compounds found in food and the environment that are capable of mimicking some of the effects of endogenous estrogens or interfering with estrogen signaling pathways by interacting with two estrogen receptors (ERs): ERα and ERβ (Pelekanou and Leclercq, 2011; Kerdivel et al, 2013). EDCs that target ER signaling can induce ER activity directly or indirectly through three signal pathways: directly through interactions with ERs, indirectly through transcription factors such as aryl hydrocarbon receptor (AhR), or through modulation of metabolic enzymes that are critical for normal estrogen synthesis and metabolism (Bidgoli et al, 2011; Shanle and Xu, 2011). TCDD, as a kind of EDC, has multiple endocrine activities and has been known to increase the incidence of breast cancer in regions contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) (Warner et al, 2002). After dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), the complex binds to the

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