The C-terminal domain of canstatin suppresses in vivo tumor growth associated with proliferation of endothelial cells.
Angiogenesis is crucial for the growth and metastasis of solid tumors with sizes larger than a few cubic millimeter Canstatin, the non-collagenous 1 (NC1) domain of alpha2 chain of type IV collagen, was previously shown to inhibit proliferation of endothelial cells in vitro and suppress in vivo tumor growth. Our previous studies showed that canstatin-N, the N-terminal 1-89 amino acid fragment of canstatin, inhibited the neovascularization in vivo, potently induced apoptosis of endothelial cells in vitro, and suppressed in vivo tumor growth in BALB/c mice. In the present study, we demonstrated that canstatin-C, the C-terminal 157-227 amino acid fragment of canstatin, also specifically inhibited in vitro the proliferation of human umbilical vein endothelial cells and induced apoptosis, but the apoptosis-inducing activity, while close to that of the full-length canstatin, was much lower than that of canstatin-N. Canstatin-C also suppressed in vivo tumor growth in BALB/c mice at a dosage of 10mg/kg/day. These results suggest that canstatin-C is an anti-angiogenic domain of canstatin mainly associated with the specific inhibition of proliferation of endothelial cells, whereas canstatin-N with the potential apoptosis-inducing activity on endothelial cells.
He
Guo-An
GA
Department of Biochemistry, The Key Laboratory of Genetic Engineering of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, PR China.
Luo
Jin-Xian
JX
Zhang
Tian-Yuan
TY
Hu
Zhi-Shang
ZS
Wang
Fang-Yu
FY
D020533:Angiogenesis Inhibitors / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002642:Chick Embryo; D024141:Collagen Type IV / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D024141:Collagen Type IV; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A