title: IGFBP-4 anti-angiogenic and anti-tumorigenic effects are associated with anti-cathepsin B activity.
abstract: Insulin-like growth factor-binding protein 4 (IGFBP-4/IBP-4) has potent IGF-independent anti-angiogenic and antitumorigenic effects. In this study, we demonstrated that these activities are located in the IGFBP-4 C-terminal protein fragment (CIBP-4), a region containing a thyroglobulin type 1 (Tg1) domain. Proteins bearing Tg1 domains have been shown to inhibit cathepsins, lysosomal enzymes involved in basement membrane degradation and implicated in tumor invasion and angiogenesis. In our studies, CIBP-4 was shown to internalize and co-localize with lysosomal-like structures in both endothelial cells (ECs) and glioblastoma U87MG cells. CIBP-4 also inhibited both growth factor-induced EC tubulogenesis in Matrigel and the concomitant increases in intracellular cathepsin B (CatB) activity. In vitro assays confirmed CIBP-4 capacity to block recombinant CatB activity. Biodistribution analysis of intravenously injected CIBP-4-Cy5.5 in a glioblastoma tumor xenograft model indicated targeted accumulation of CIBP-4 in tumors. Most importantly, CIBP-4 reduced tumor growth in this animal model by 60%. Pleiotropic anti-angiogenic and anti-tumorigenic activities of CIBP-4 most likely underlie its observed therapeutic potential against glioblastoma.
authors: National Research Council of Canada, Ottawa, Ontario, Canada. maria.moreno@nrc.ca
authors: María J
authors: MJ
authors: Moreno
authors: Marguerite
authors: M
authors: Ball
authors: Marina
authors: M
authors: Rukhlova
authors: Jacqueline
authors: J
authors: Slinn
authors: Denis
authors: D
authors: L'abbe
authors: Umar
authors: U
authors: Iqbal
authors: Robert
authors: R
authors: Monette
authors: Martin
authors: M
authors: Hagedorn
authors: Maureen D
authors: MD
authors: O'Connor-McCourt
authors: Yves
authors: Y
authors: Durocher
authors: Danica B
authors: DB
authors: Stanimirovic
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C584416:CIBP-4 peptide; D018974:Insulin-Like Growth Factor Binding Protein 4; D010446:Peptide Fragments; C533912:CTSB protein, human; D002401:Cathepsin B
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