Abstract
The fibulins are a family of secreted glycoproteins that are characterized by repeated epidermal-growth-factor-like domains and a unique C-terminus structure. Fibulins modulate cell morphology, growth, adhesion, and motility. Our initial basement membrane degradome screen using Cathepsin D, a tumor microenvironment-associated protease, contained fragments of fibulin-1 and full length fibulin-5. In this report, we evaluate the anti-angiogenic activity of fibulin-1 and fibulin-5. Tumor studies demonstrate that both fibulin-1 and fibulin-5 suppress HT1080 tumor growth. CD31 labeling and TUNEL assay further reveal that fibulin-1 suppression of HT1080 tumor growth is associated with diminished angiogenesis and also enhanced apoptosis of endothelial cells and tumor cells. In contrast, fibulin-5 inhibits tumor angiogenesis with a minimal anti-apoptotic affect. Cathepsin D digestion of fibulin-1 produces a fragment with nearly the same molecular weight as fibulin-5, and this fragment (named Neostatin) inhibits endothelial cell proliferation. Additionally, degradation of basement membrane by cathepsin D liberates both fibulin-1 fragments and fibulin-5, which function to inhibit angiogenesis.
Original language | English (US) |
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Pages (from-to) | 155-162 |
Number of pages | 8 |
Journal | Experimental Biology and Medicine |
Volume | 233 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2008 |
Externally published | Yes |
Keywords
- Angiogenesis
- Basement membrane
- Cancer
- Fibulin
- Neostatin
- Tumor
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology