Galectin-3 (Gal-3) is a β-galactoside-binding protein that influences various cell functions, including cell adhesion. We focused on the role of Gal-3 as an extracellular ligand mediating cell-matrix adhesion. We used human adipose tissue-derived stem cells and human umbilical vein endothelial cells that are promising for vascular tissue engineering. We found that these cells naturally contained Gal-3 on their surface and inside the cells. Moreover, they were able to associate with exogenous Gal-3 added to the culture medium. This association was reduced with a β-galactoside LacdiNAc (GalNAcβ1,4GlcNAc), a selective ligand of Gal-3, which binds to the carbohydrate recognition domain (CRD) in the Gal-3 molecule. This ligand was also able to detach Gal-3 newly associated with cells but not Gal-3 naturally present on cells. In addition, Gal-3 preadsorbed on plastic surfaces acted as an adhesion ligand for both cell types, and the cell adhesion was resistant to blocking with LacdiNAc. This result suggests that the adhesion was mediated by a binding site different from the CRD. The blocking of integrin adhesion receptors on cells with specific antibodies revealed that the cell adhesion to the preadsorbed Gal-3 was mediated, at least partially, by β1 and αV integrins—namely α5β1, αVβ3, and αVβ1 integrins.
Galectin-3
(Gal-3) participates in many cancer-related metabolic
processes. The inhibition of overexpressed Gal-3 by, e.g., β-galactoside-derived
inhibitors is hence promising for cancer treatment. The multivalent
presentation of such inhibitors on a suitable biocompatible carrier
can enhance the overall affinity to Gal-3 and favorably modify the
interaction with Gal-3-overexpressing cells. We synthesized a library
of C-3 aryl-substituted thiodigalactoside inhibitors and their multivalent N-(2-hydroxypropyl)methacrylamide (HPMA)-based counterparts
with two different glycomimetic contents. Glycopolymers with a higher
content of glycomimetic exhibited a higher affinity to Gal-3 as assessed
by ELISA and biolayer interferometry. Among them, four candidates
(with 4-acetophenyl, 4-cyanophenyl, 4-fluorophenyl, and thiophen-3-yl
substitution) were selected for further evaluation in cancer-related
experiments in cell cultures. These glycopolymers inhibited Gal-3-induced
processes in cancer cells. The cyanophenyl-substituted glycopolymer
exhibited the strongest antiproliferative, antimigratory, antiangiogenic,
and immunoprotective properties. The prepared glycopolymers appear
to be prospective modulators of the tumor microenvironment applicable
in the therapy of Gal-3-associated cancers.
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