Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway,Journal of Advanced Research

当前位置： X-MOL 学术 › J. Adv. Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2022-06-16 , DOI: 10.1016/j.jare.2022.06.006
Juping Zhang ₁ , Neng Wang ₂ , Yifeng Zheng ₁ , Bowen Yang ₁ , Shengqi Wang ₃ , Xuan Wang ₁ , Bo Pan ₁ , Zhiyu Wang ₄

Affiliation

Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510006, Guangdong, China.
Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China; The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China.
Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510006, Guangdong, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China.
Integrative Research Laboratory of Breast Cancer, Discipline of Integrated Chinese and Western Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510006, Guangdong, China; The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China.

Introduction

Chronic psychological stress is a well-established risk factor for breast cancer development. Si-Ni-San (SNS) is a classical traditional Chinese medicine formula prescribed to psychological disorder patients. However, its action effects, molecular mechanisms, and bioactive phytochemicals against breast cancer are not yet clear.

Objectives

This study aimed to explore the modulatory mechanism and bioactive compound of SNS in regulating estrogen metabolism during breast cancer development induced by chronic psychological stress.

Methods

Mouse breast cancer xenograft was used to determine the effect of SNS on breast cancer growth and metastasis. Metabolomics analysis was conducted to discover the impact of SNS on metabolic profile changes in vivo. Multiple molecular biology experiments and breast cancer xenografts were applied to verify the anti-metastatic potentials of the screened bioactive compound.

Results

SNS remarkably inhibited chronic psychological stress-induced breast cancer growth and metastasis in the mouse breast cancer xenograft. Meanwhile, chronic psychological stress increased the level of cholic acid, accompanied by the elevation of estradiol. Mechanistic investigation demonstrated that cholic acid activated farnesoid X receptor (FXR) expression, which inhibited hepatocyte nuclear factor 4α (HNF4α)-mediated estrogen sulfotransferase (EST) transcription in hepatocytes, and finally resulting in estradiol elevation. Notably, SNS inhibited breast cancer growth by suppressing estradiol level via modulating FXR/EST signaling. Furthermore, luciferase-reporting gene assay screened naringenin as the most bioactive compound in SNS for triggering EST activity in hepatocytes. Interestingly, pharmacokinetic study revealed that naringenin had the highest absorption in the liver tissue. Following in vivo and in vitro studies demonstrated that naringenin inhibited stress-induced breast cancer growth and metastasis by promoting estradiol metabolism via FXR/EST signaling.

Conclusion

This study not only highlights FXR/EST signaling as a crucial target in mediating stress-induced breast cancer development, but also provides naringenin as a potential candidate for breast cancer endocrine therapy via promoting estradiol metabolism.

中文翻译：

Si-Ni-San配方柚皮素通过FXR/EST途径调节雌激素代谢抑制慢性心理应激诱导的乳腺癌生长和转移

介绍

慢性心理压力是乳腺癌发展的公认危险因素。四逆散 (SNS) 是治疗心理障碍患者的经典中药方剂。然而，其抗乳腺癌的作用效果、分子机制和生物活性植物化学物质尚不清楚。

目标

本研究旨在探讨SNS在慢性心理应激诱导的乳腺癌发展过程中调节雌激素代谢的调节机制和生物活性成分。

方法

小鼠乳腺癌异种移植物用于确定 SNS 对乳腺癌生长和转移的影响。进行代谢组学分析以发现 SNS 对体内代谢谱变化的影响。应用多个分子生物学实验和乳腺癌异种移植物来验证筛选的生物活性化合物的抗转移潜力。

结果

SNS 显着抑制小鼠乳腺癌异种移植物中慢性心理应激诱导的乳腺癌生长和转移。同时，长期的心理压力增加了胆酸水平，并伴随着雌二醇的升高。机制研究表明，胆酸激活法尼醇 X 受体 (FXR) 表达，抑制肝细胞核因子 4α (HNF4α) 介导的肝细胞雌激素磺基转移酶 (EST) 转录，最终导致雌二醇升高。值得注意的是，SNS通过抑制雌二醇水平来抑制乳腺癌的生长调制 FXR/EST 信号。此外，荧光素酶报告基因分析筛选出柚皮素是 SNS 中最具生物活性的化合物，可触发肝细胞中的 EST 活性。有趣的是，药代动力学研究显示柚皮素在肝组织中的吸收最高。体内和体外研究表明，柚皮素通过FXR/EST 信号促进雌二醇代谢，从而抑制应激诱导的乳腺癌生长和转移。