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J. Biol. Chem., Vol. 283, Issue 32, 22177-22185, August 8, 2008

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Sialylation of β1 Integrins Blocks Cell Adhesion to Galectin-3 and Protects Cells against Galectin-3-induced Apoptosis^*

Ya Zhuo, Roger Chammas, and Susan L. Bellis¹

From the Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294 and the Faculdade de Medicina da Universidade de São Paulo, CEP 01246903 São Paulo, Brazil

In previous studies, we determined that β1 integrins from human colon tumors have elevated levels of 2-6 sialylation, a modification added by β-galactosamide -2,6-sialyltranferase I (ST6Gal-I). Intriguingly, the β1 integrin is thought to be a ligand for galectin-3 (gal-3), a tumor-associated lectin. The effects of gal-3 are complex; intracellular forms typically protect cells against apoptosis through carbohydrate-independent mechanisms, whereas secreted forms bind to cell surface oligosaccharides and induce apoptosis. In the current study, we tested whether 2-6 sialylation of the β1 integrin modulates binding to extracellular gal-3. Herein we report that SW48 colonocytes lacking 2-6 sialylation exhibit β1 integrin-dependent binding to gal-3-coated tissue culture plates; however, binding is attenuated upon forced expression of ST6Gal-I. Removal of 2-6 sialic acids from ST6Gal-I expressors by neuraminidase treatment restores gal-3 binding. Additionally, using a blot overlay approach, we determined that gal-3 binds directly and preferentially to unsialylated, as compared with 2-6-sialylated, β1 integrins. To understand the physiologic consequences of gal-3 binding, cells were treated with gal-3 and monitored for apoptosis. Galectin-3 was found to induce apoptosis in parental SW48 colonocytes (unsialylated), whereas ST6Gal-I expressors were protected. Importantly, gal-3-induced apoptosis was inhibited by function blocking antibodies against the β1 subunit, suggesting that β1 integrins are critical transducers of gal-3-mediated effects on cell survival. Collectively, our results suggest that the coordinate up-regulation of gal-3 and ST6Gal-I, a feature that is characteristic of colon carcinoma, may confer tumor cells with a selective advantage by providing a mechanism for blockade of the pro-apoptotic effects of secreted gal-3.

Received for publication, January 2, 2008 , and in revised form, June 12, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01CA84248 (to S. L. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 982A MCLM, 1918 University Blvd., Birmingham, AL 35294. Tel.: 205-934-3441; Fax: 205-975-9028; E-mail: bellis{at}physiology.uab.edu.

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