Glycyrrhetinic acid suppresses breast cancer metastasis by inhibiting M2-like macrophage polarization via activating JNK1/2 signaling

Cheng，Yanfen1; Zhong，Xuemei1; Nie，Xin4; Gu，Huan1; Wu，Xiaoping2; Li，Renkai2; Wu，Yihan1; Lv，Kongpeng3; Leung，George Pak Heng2; Fu，Chaomei1; Lee，Simon Ming Yuen4; Zhang，Jinming1; Li，Jingjing1,2

2023-06-01

10.1016/j.phymed.2023.154757

Phytomedicine   Impact Factor & Quartile

0944-7113

1618-095X

Background: Breast cancer metastasis is leading cause of cancer death among women worldwide. Tumor-associated macrophages (TAMs) have been considered as potential targets for treating breast cancer metastasis because they promote tumor growth and development. Glycyrrhetinic acid (GA) is one of the most important phytochemicals of licorice which has shown promising anti-cancer efficacies in pre-clinical trials. However, the regulatory effect of GA on the polarization of TAMs remains elusive. Purpose: To investigate the role of GA in regulating the polarization of M2 macrophages and inhibiting breast cancer metastasis, and to further explore its underlying mechanisms of action. Study Design: IL-4 / IL-13-treated RAW 264.7 and THP-1 cells were used as the M2-polarized macrophages in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were applied to study the effect of GA on breast cancer growth and metastasis in vivo. Results: In vitro studies showed that GA significantly inhibited IL-4 / IL 13-induced M2-like polarization in RAW 264.7 and THP-1 macrophages without affecting M1-like polarization. GA strongly decreased the expression of M2 macrophage markers CD206 and Arg-1, and reduced the levels of the pro-angiogenic molecules VEGF, MMP9, MMP2 and IL-10 in M2 macrophages. GA also increased the phosphorylation of JNK1/2 in M2 macrophages. Moreover, GA significantly suppressed M2 macrophage-induced cell proliferation and migration in 4T1 cancer cells and HUVECs. Interestingly, the inhibitory effects of GA on M2 macrophages were abolished by a JNK inhibitor. Animal studies showed that GA significantly suppressed tumor growth, angiogenesis, and lung metastasis in BALB/c mice bearing breast tumor. In tumor tissues, GA reduced the number of M2 macrophages but elevated the proportion of M1 macrophages, accompanied by activation of JNK signaling. Similar results were found in the tail vein breast cancer metastasis model. Conclusion: This study demonstrated for the first time that GA could effectively suppress breast cancer growth and metastasis by inhibiting macrophage M2 polarization via activating JNK1/2 signaling. These findings indicate that GA could be served as the lead compound for the future development of anti-breast cancer drug.

Angiogenesis Breast cancer metastasis Glycyrrhetinic acid JNK1/2 pathway Tumor-associated macrophages

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China Postdoctoral Science Foundation[2022M710499];National Natural Science Foundation of China[81973662];National Natural Science Foundation of China[82104462];National Natural Science Foundation of China[82274112];

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85151406746

Scopus

1.State Key Laboratory of Southwestern Chinese Medicine Resources,School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu,China
2.Department of Pharmacology and Pharmacy,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong SAR,China
3.Department of Interventional Radiology,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University; The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,China
4.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences,University of Macau,Macao SAR,China

Cheng，Yanfen,Zhong，Xuemei,Nie，Xin,et al. Glycyrrhetinic acid suppresses breast cancer metastasis by inhibiting M2-like macrophage polarization via activating JNK1/2 signaling[J]. Phytomedicine,2023,114.

Cheng，Yanfen.,Zhong，Xuemei.,Nie，Xin.,Gu，Huan.,Wu，Xiaoping.,...&Li，Jingjing.(2023).Glycyrrhetinic acid suppresses breast cancer metastasis by inhibiting M2-like macrophage polarization via activating JNK1/2 signaling.Phytomedicine,114.

Cheng，Yanfen,et al."Glycyrrhetinic acid suppresses breast cancer metastasis by inhibiting M2-like macrophage polarization via activating JNK1/2 signaling".Phytomedicine 114(2023).