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Carcinogenesis Advance Access originally published online on November 4, 2004
Carcinogenesis 2005 26(2):309-318; doi:10.1093/carcin/bgh329
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Carcinogenesis vol.26 no.2 © Oxford University Press 2005; all rights reserved.

ARTICLE

Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion

Jun Zou1, Vladislav V. Glinsky1,2, Linda A. Landon2, Leslie Matthews3 and Susan L. Deutscher1,2,*

1 Department of Biochemistry, University of Missouri, Columbia, MO 65212, USA, 2 Harry S.Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA and 3 Dana-Farber Cancer Institute, Boston, MA 02115, USA

* To whom correspondence should be addressed at: Department of Biochemistry, M743 Medical Sciences Building, Columbia, MO 65212, USA. Tel: +1 573 882 2454; Fax: +1 573 884 4597; Email: deutschers{at}missouri.edu

Intravascular cancer cell adhesion plays a significant role in the metastatic process. Studies indicate that galectin-3, a member of the galectin family of soluble animal lectins, is involved in carbohydrate-mediated metastatic cell heterotypic (between carcinoma cells and endothelium) and homotypic (between carcinoma cells) adhesion via interactions with the tumor-specific Thomsen–Friedenreich glycoantigen (TFAg). We hypothesized that blocking the galectin-3 carbohydrate recognition domain with synthetic peptides would significantly reduce metastasis-associated carcinoma cell adhesion. To test this hypothesis, we identified peptide antagonists of the galectin-3 carbohydrate recognition domain using combinatorial bacteriophage display technology. The peptides bound with high affinity to purified recombinant galectin-3 protein (Kd {approx} 17–80 nM) and to cell surface galectin-3. Experiments with a series of recombinant serially truncated galectin-3 mutants indicated that the peptides bound the carbohydrate recognition domain of galectin-3. Furthermore, the peptides did not bind the carbohydrate recognition domain of other galectins and plant lectins. Synthetic galectin-3 carbohydrate recognition domain-specific peptides blocked the interaction between galectin-3 and TFAg and significantly inhibited rolling and stable heterotypic adhesion of human MDA-MB-435 breast carcinoma cells to endothelial cells under flow conditions, as well as homotypic tumor cell aggregation. These results demonstrate that carbohydrate-mediated, metastasis-associated tumor cell adhesion could be inhibited efficiently with short synthetic peptides which do not mimic naturally occurring glycoepitopes yet bind to the galectin-3 carbohydrate recognition domain with high affinity and specificity.


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