Integrin alpha2beta1 mediates the anti-angiogenic and anti-tumor activities of angiocidin, a novel tumor-associated protein.
We recently characterized an anti-tumor protein termed angiocidin. Here, we report that angiocidin may inhibit angiogenesis by binding collagen and its receptors. Angiocidin bound purified type I collagen and alpha2beta1 with high affinity. K562 cells expressing alpha2beta1 bound and adhered to angiocidin while K562 cells which only expressed alpha5beta1 integrin showed no binding and adhesion. Binding was specific since a neutralizing antibody against alpha2beta1 inhibited binding but antibodies against alpha5beta1 had no effect. Additionally, angiocidin co-localized with alpha2beta1 on K562 alpha2beta1 transfected cells, pancreatic cancer colo 357 cells, breast cancer MB-231 cells and human umbilical endothelial vein (HUVE) cells. In an alpha2beta1-dependent collagen gel angiogenesis assay, angiocidin showed potent inhibitory activity. We identified a 20-amino-acid amino terminal peptide of angiocidin that bound both alpha2beta1 and type I collagen. This peptide promoted alpha2beta1-dependent cell adhesion and inhibited tumor growth and angiogenesis. Taken together, these results are consistent with the conclusion that the anti-tumor activity of angiocidin arises from its ability to ligate collagen and alpha2beta1 on endothelial cells and tumor cells. Our results provide support for the concept that targeting matrix-cell interactions is a viable strategy for the development of anti-cancer therapeutics.
Sabherwal
Yamini
Y
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
Rothman
Vicki L
VL
Dimitrov
Svetoslav
S
L'Heureux
Darryl Z
DZ
Marcinkiewicz
Cezary
C
Sharma
Mahesh
M
Tuszynski
George P
GP
D000596:Amino Acids / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D024042:Collagen Type I / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D039222:Integrin alpha1beta1 / Q000378:metabolism; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D020014:K562 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D016601:RNA-Binding Proteins; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D039222:Integrin alpha1beta1; D038982:Integrin alpha2beta1; D009363:Neoplasm Proteins; C498506:PSMD4 protein, human; D010455:Peptides; D016601:RNA-Binding Proteins; D046988:Proteasome Endopeptidase Complex