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
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 migh...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823003420 |
| _version_ | 1797422679620321280 |
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| author | Weiwei Zheng Peiliang Shen Chang Yu Yu Tang Cheng Qian Chunmei Yang Mingliang Gao Yuanyuan Wu Suyun Yu Weiwei Tang Guiping Wan Aiyun Wang Yin Lu Yang Zhao |
| author_facet | Weiwei Zheng Peiliang Shen Chang Yu Yu Tang Cheng Qian Chunmei Yang Mingliang Gao Yuanyuan Wu Suyun Yu Weiwei Tang Guiping Wan Aiyun Wang Yin Lu Yang Zhao |
| author_sort | Weiwei Zheng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T07:36:52Z |
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| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-09T07:36:52Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-fdb62cd59ac04a28878a80401b7d2f892023-12-03T05:39:38ZengElsevierPharmacological Research1096-11862023-12-01198106986Ginsenoside 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 barrierWeiwei Zheng0Peiliang Shen1Chang Yu2Yu Tang3Cheng Qian4Chunmei Yang5Mingliang Gao6Yuanyuan Wu7Suyun Yu8Weiwei Tang9Guiping Wan10Aiyun Wang11Yin Lu12Yang Zhao13Jiangsu 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, ChinaJiangsu 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, ChinaDepartment of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaDepartment of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu 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, ChinaDepartment 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, ChinaDepartment 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, ChinaJiangsu 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; Corresponding authors at: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.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; Corresponding authors at: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.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; Corresponding authors at: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.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.http://www.sciencedirect.com/science/article/pii/S1043661823003420Ginsenoside Rh1Tumor cell extravasationCCL20Endothelial permeabilityHHEXCK2α |
| spellingShingle | Weiwei Zheng Peiliang Shen Chang Yu Yu Tang Cheng Qian Chunmei Yang Mingliang Gao Yuanyuan Wu Suyun Yu Weiwei Tang Guiping Wan Aiyun Wang Yin Lu Yang Zhao 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 Pharmacological Research Ginsenoside Rh1 Tumor cell extravasation CCL20 Endothelial permeability HHEX CK2α |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Ginsenoside Rh1 Tumor cell extravasation CCL20 Endothelial permeability HHEX CK2α |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823003420 |
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