Abstract
Both mucin 1 (MUC1) and galectin-3 are known to be overexpressed in various malignant tumors and associated with a poor prognosis. It has been extensively reported that MUC1 is involved in potentiation of growth factor-dependent signal transduction. Because some carbohydrate moieties carried on MUC1 change to preferable ones for binding of galectin-3 in cancer cells, we speculated that MUC1-mediated signaling may occur through direct binding of galectin-3. Immunochemical studies showed that the distribution of galectin-3 coincided with that of MUC1 in various human tumor tissues but not in human nonmalignant tissues, and the level of galectin-3 retained on the surface of various cancer cells paralleled that of MUC1. Treatment of MUC1-expressing cells with galectin-3 induced phosphorylation of ERK1/2 and Akt following enhanced phosphorylation of MUC1 C-terminal domain, consistently promoting tumor cell malignancy. It is also noted that this enhanced phosphorylation occurred independently of EGF receptor-mediated signaling in both EGF receptor- and MUC1-expressing cells, and multivalency of galectin-3 was important for initiation of MUC1-mediated signaling. Expectedly, both silencing of endogenous galectin-3 and treatment with galectin-3 antagonists down-regulated cell proliferation of MUC1-expressing cells. These results suggest that the binding of galectin-3 to MUC1 plays a key role in MUC1-mediated signaling. Thus, constitutive activation of MUC1-mediated signaling in an autocrine/paracrine manner caused by ligation of galectin-3 promotes uncontrolled tumor cell malignancy. This signaling may be another MUC1-mediated pathway and function in parallel with a growth factor-dependent MUC1-mediated signaling pathway.
Highlights
Both mucin 1 (MUC1) and galectin-3 are overexpressed in various malignant tumors
We demonstrated that galectin-3 was distributed with MUC1 in various human tumor tissues and on the surface of cancer cells and that extracellular galectin-3 retained on the cell surface approximately paralleled the level of MUC1, suggesting that galectin-3 binds to MUC1 on the cell surface
MUC1 Is Distributed with Galectin-3 on the Surface of Cancer Cells and in Human Tumor Tissues—To date, many mucin and galectin family members have been identified in mammals [2, 10]
Summary
Both MUC1 and galectin-3 are overexpressed in various malignant tumors. Results: Binding of galectin-3 to MUC1 enhances the phosphorylation of ERK1/2 and Akt, promoting tumor cell malignancy. Constitutive activation of MUC1-mediated signaling in an autocrine/paracrine manner caused by ligation of galectin-3 promotes uncontrolled tumor cell malignancy This signaling may be another MUC1-mediated pathway and function in par-. The interaction of galectin-3 with MUC1 induces polarization of MUC1 on the cell surface and resultant exposure of cell adhesion molecules, leading to homotypic aggregation of cancer cells or adhesion of cancer cells to endothelial cells (28 –30) These studies have provided no insights into the downstream signaling by MUC1 after the binding of galectin-3. An EGFR inhibitor had no effect on these signaling pathways These results suggest that galectin-3 may play a significant role as a potential endogenous ligand for activation of MUC1-mediated signaling in an autocrine/paracrine manner and that this signaling may be another MUC1-mediated pathway and function in parallel with a growth factor-dependent MUC1-mediated signaling pathway
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