title: RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation.
abstract: Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer.
authors.affiliation: Institute of Chinese Medicine.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK).
authors.forename: Hoi-Wing
authors.initials: HW
authors.lastname: Leung
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Si-Meng
authors.initials: SM
authors.lastname: Zhao
authors.affiliation: Institute of Chinese Medicine.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK).
authors.forename: Grace Gar-Lee
authors.initials: GG
authors.lastname: Yue
authors.affiliation: Institute of Chinese Medicine.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK).
authors.forename: Julia Kin-Ming
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Institute of Chinese Medicine.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK).|School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: Institute of Chinese Medicine.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK).
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Leung
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China.
authors.forename: Ning-Hua
authors.initials: NH
authors.lastname: Tan
authors.affiliation: Institute of Chinese Medicine.|State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK).
authors.forename: Clara Bik-San
authors.initials: CB
authors.lastname: Lau
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051338:Cofilin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D016023:Integrins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008207:Lymphatic Metastasis; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051338:Cofilin 1; D016213:Cyclins; D016326:Extracellular Matrix Proteins; D016023:Integrins; D010456:Peptides, Cyclic; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C081563:RA XII; D020928:Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9