title: Deguelin inhibits vasculogenic function of endothelial progenitor cells in tumor progression and metastasis via suppression of focal adhesion.
abstract: Deguelin is a nature-derived chemopreventive drug. Endothelial progenitor cells (EPCs) are bone-marrow (BM)-derived key components to induce new blood vessels in early tumorigenesis and metastasis. Here we determined whether deguelin inhibits EPC function in vitro and in vivo at doses not affecting cancer cell apoptosis. Deguelin significantly reduced the number of EPC colony forming units of BM-derived c-kit+/sca-1+ mononuclear cells (MNCs), proliferation, migration, and adhesion to endothelial cell monolayers, and suppressed incorporation of EPC into tube-like vessel networks when co-cultured with endothelial cells. Deguelin caused cell cycle arrest at G1 without induction of apoptosis in EPC. In a mouse tumor xenograft model, tumor growth, lung metastasis and tumor-induced circulating EPCs were supressed by deguelin treatment (2 mg/kg). In mice tranplanted with GFP-expressing BM-MNCs, deguelin reduced the co-localization of CD31 and GFP, suggesting suppression of BM-derived EPC incoporation into tumor vessels. Interestingly, focal adhesion kinase (FAK)-integrin-linked kinase (ILK) activation and actin polymerization were repressed by deguelin. Decreased number of focal adhesions and a depolarized morphology was found in deguelin-treated EPCs. Taken together, our results suggest that the deguelin inhibits tumorigenesis and metastasis via EPC suppression and that suppression of focal adhesion by FAK-integrin-ILK-dependent actin remodeling is a key underlying molecular mechanism.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea.|School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Minh Phuong
authors.initials: MP
authors.lastname: Nguyen
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Dongjin
authors.initials: D
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Se-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: Hye-Eun
authors.initials: HE
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea.|School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D066026:Endothelial Progenitor Cells / Q000166:cytology*; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099200:Scaffold Protein ILK
chemical_list: D000199:Actins; D020533:Angiogenesis Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D049452:Green Fluorescent Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D012402:Rotenone; D000099200:Scaffold Protein ILK; C107676:deguelin
keywords: actin remodeling; deguelin; endothelial progenitor cells; focal adhesion; tumor vasculogenesis