Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells

• Published in: The Journal of biological chemistry 2017-05, Vol.292 (20), p.8381-8389
• Main Authors: Colomb, Florent, Wang, Weikun, Simpson, Deborah, Zafar, Mudaser, Beynon, Robert, Rhodes, Jonathan M., Yu, Lu-Gang
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Antigens, CD - metabolism; Cadherins - genetics; Cadherins - metabolism; carbohydrate-binding protein; CD146; CD146 Antigen - genetics; CD146 Antigen - metabolism; cytokine; endothelium; galectin; Galectin 3 - genetics; Galectin 3 - metabolism; galectin-3; Glycobiology and Extracellular Matrices; Granulocyte Colony-Stimulating Factor - genetics; Granulocyte Colony-Stimulating Factor - metabolism; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; IL-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; MCAM; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Platelet Endothelial Cell Adhesion Molecule-1 - genetics; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Protein Multimerization
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M117.783431

The galactoside-binding protein galectin-3 is increasingly recognized as an important player in cancer development, progression, and metastasis via its interactions with various galactoside-terminated glycans. We have shown previously that circulating galectin-3, which is increased up to 30-fold in cancer patients, promotes blood-borne metastasis in an animal cancer model. This effect is partly attributable to the interaction of galectin-3 with unknown receptor(s) on vascular endothelial cells and causes endothelial secretion of several metastasis-promoting cytokines. Here we sought to identify the galectin-3-binding molecule(s) on the endothelial cell surface responsible for the galectin-3-mediated cytokine secretion. Using two different galectin-3 affinity purification processes, we extracted four cell membrane glycoproteins, CD146/melanoma cell adhesion molecule (MCAM)/MUC18, CD31/platelet endothelial cell adhesion molecule-1 (PECAM-1), CD144/VE-cadherin, and CD106/Endoglin, from vascular endothelial cells. CD146 was the major galectin-3-binding ligand and strongly co-localized with galectin-3 on endothelial cell surfaces treated with exogenous galectin-3. Moreover, galectin-3 bound to N-linked glycans on CD146 and induced CD146 dimerization and subsequent activation of AKT signaling. siRNA-mediated suppression of CD146 expression completely abolished the galectin-3-induced secretion of IL-6 and G-CSF cytokines from the endothelial cells. Thus, CD146/MCAM is the functional galectin-3-binding ligand on endothelial cell surfaces responsible for galectin-3-induced secretion of metastasis-promoting cytokines. We conclude that CD146/MCAM interactions with circulating galectin-3 may have an important influence on cancer progression and metastasis.