Deguelin inhibits vasculogenic function of endothelial progenitor cells in tumor progression and metastasis via suppression of focal adhesion
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Minh Phuong Nguyen1,3, Dongjin Lee1, Se-Hyung Lee1, Hye-Eun Lee1, Ho-Young Lee2, You Mie Lee1,3
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702–701, Republic of Korea
2College of Pharmacy, Seoul National University, Seoul, 151–742, Republic of Korea
3School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702–701, Republic of Korea
You Mie Lee, e-mail: firstname.lastname@example.org
Keywords: deguelin, endothelial progenitor cells, tumor vasculogenesis, focal adhesion, actin remodeling
Received: March 4, 2015 Accepted: April 14, 2015 Published: April 27, 2015
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.
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