title: Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis.
abstract: Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.
authors: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
authors: Masanari
authors: M
authors: Obika
authors: Hiroko
authors: H
authors: Ogawa
authors: Katsuyuki
authors: K
authors: Takahashi
authors: Jiayi
authors: J
authors: Li
authors: Omer Faruk
authors: OF
authors: Hatipoglu
authors: Mehmet Zeynel
authors: MZ
authors: Cilek
authors: Toru
authors: T
authors: Miyoshi
authors: Junko
authors: J
authors: Inagaki
authors: Takashi
authors: T
authors: Ohtsuki
authors: Shozo
authors: S
authors: Kusachi
authors: Yoshifumi
authors: Y
authors: Ninomiya
authors: Satoshi
authors: S
authors: Hirohata
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000818:Animals; D015153:Blotting, Western; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000201:enzymology*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D051381:Rats; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human