2. Academic Validation
  3. Ginsenoside Rh1, a novel casein kinase II subunit alpha (CK2α) inhibitor, retards metastasis via disrupting HHEX/CCL20 signaling cascade involved in tumor cell extravasation across endothelial barrier

Ginsenoside Rh1, a novel casein kinase II subunit alpha (CK2α) inhibitor, retards metastasis via disrupting HHEX/CCL20 signaling cascade involved in tumor cell extravasation across endothelial barrier

  • Pharmacol Res. 2023 Nov 7:106986. doi: 10.1016/j.phrs.2023.106986.
Weiwei Zheng 1,  Peiliang Shen 1,  Chang Yu 2,  Yu Tang 3,  Cheng Qian 3,  Chunmei Yang 2,  Mingliang Gao 3,  Yuanyuan Wu 3,  Suyun Yu 1,  Weiwei Tang 4,  Guiping Wan 4,  Aiyun Wang 5,  Yin Lu 6,  Yang Zhao 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; Department of Obstetrics and Gynecology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
  • 5 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: wangaiyun@njucm.edu.cn.
  • 6 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: luyingreen@njucm.edu.cn.
  • 7 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: y.zhao@njucm.edu.cn.
PMID: 37944834 DOI: 10.1016/j.phrs.2023.106986
Abstract

Tumor cell extravasation across endothelial barrier has been recognized as a pivotal event in orchestrating metastasis formation. This event is initiated by the interactions of extravasating tumor cells with endothelial cells (ECs). Therefore, targeting the crosstalk between tumor cells and ECs might be a promising therapeutic strategy to prevent metastasis. In this study, we demonstrated that Rh1, one of the main ingredients of ginseng, hindered the invasion of breast Cancer (BC) cells as well as diminished the permeability of ECs both in vitro and in vivo, which was responsible for the attenuated tumor cell extravasation across endothelium. Noteworthily, we showed that ECs were capable of inducing the epithelial-mesenchymal transition (EMT) and invadopodia of BC cells that are essential for tumor cell migration and invasion through limiting the nuclear translocation of hematopoietically expressed homeobox (HHEX). The decreased nuclear HHEX paved the way for initiating the CCL20/CCR6 signaling axis, which in turn contributed to damaged endothelial junctions, uncovering a new crosstalk mode between tumor cells and ECs. Intriguingly, Rh1 inhibited the kinase activity of Casein Kinase II subunit alpha (CK2α) and further promoted the nuclear translocation of HHEX in the BC cells, which resulted in the disrupted crosstalk between chemokine (C-C motif) ligand 20 (CCL20) in the BC cells and chemokine (C-C motif) receptor 6 (CCR6) in the ECs. The prohibited CCL20-CCR6 axis by Rh1 enhanced vascular integrity and diminished tumor cell motility. Taken together, our data suggest that Rh1 serves as an effective natural CK2α inhibitor that can be further optimized to be a therapeutic agent for reducing tumor cell extravasation.

Keywords

CCL20; CK2α; Ginsenoside Rh1; HHEX; endothelial permeability; tumor cell extravasation.

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