Endostatin binds tropomyosin. A potential modulator of the antitumor activity of endostatin

The mechanism of action of Endostatin, an endogenous inhibitor of angiogenesis and tumor growth, remains unknown. We utilized phage-display technology to identify polypeptides that mimic the binding domains of proteins with which Endostatin interacts. A conformed peptide (E37) was identified that sh...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 276; no. 27; pp. 25190 - 25196
Main Authors:	MacDonald, N J, Shivers, W Y, Narum, D L, Plum, S M, Wingard, J N, Fuhrmann, S R, Liang, H, Holland-Linn, J, Chen, D H, Sim, B K
Format:	Journal Article
Language:	English
Published:	United States 06-07-2001
Subjects:	Actin Cytoskeleton - metabolism Actins - metabolism Animals Antineoplastic Agents - metabolism Apoptosis Bacteriophages Binding Sites Cell Line Chickens Collagen - metabolism Electrophoresis, Polyacrylamide Gel endostatin Endostatins Enzyme-Linked Immunosorbent Assay Epitope Mapping Fluorescent Antibody Technique Humans Kinetics Molecular Mimicry Peptide Fragments - metabolism Rabbits Recombinant Proteins - metabolism Tropomyosin - metabolism
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Summary:	The mechanism of action of Endostatin, an endogenous inhibitor of angiogenesis and tumor growth, remains unknown. We utilized phage-display technology to identify polypeptides that mimic the binding domains of proteins with which Endostatin interacts. A conformed peptide (E37) was identified that shares an epitope with human tropomyosin implicating tropomyosin as an Endostatin-binding protein. We show that recombinant human Endostatin binds tropomyosin in vitro and to tropomyosin-associated microfilaments in a variety of endothelial cell types. The most compelling evidence that tropomyosin modulates the activity of Endostatin was demonstrated when E37 blocked greater than 84% of the tumor-growth inhibitory activity of Endostatin in the B16-BL6 metastatic melanoma model. We conclude that the E37 peptide mimics the Endostatin-binding epitope of tropomyosin and blocks the antitumor activity of Endostatin by competing for Endostatin binding. We postulate that the Endostatin interaction with tropomyosin results in disruption of microfilament integrity leading to inhibition of cell motility, induction of apoptosis, and ultimately inhibition of tumor growth.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0021-9258
DOI:	10.1074/jbc.M100743200