Galectin-3 Mediates Nuclear β-Catenin Accumulation and Wnt Signaling in Human Colon Cancer Cells by Regulation of Glycogen Synthase Kinase-3β Activity

Abstract

Wnt/B-catenin signaling plays an essential role in colon carcinogenesis. Galectin-3, a B-galactoside-binding protein, has been implicated in Wnt signaling, but the precise mechanisms by which galectin-3 modulates the Wnt pathway are unknown. In the present study, we determined the effects of galectin-3 on the Wnt/B-catenin pathway in colon cancer cells, as well as the mechanisms involved. Galectin-3 levels were manipulated in human colon cancer cells by stable transfection of galectin-3 antisense, short hairpin RNA, or fulllength galectin-3 cDNA, and effects on B-catenin levels, subcellular distribution, and Wnt signaling were determined. Galectin-3 levels correlated with B-catenin levels in a variety of colon cancer cell lines. Down-regulation of galectin-3 resulted in decreased B-catenin protein levels but no change in B-catenin mRNA levels, suggesting that galectin-3 modulates B-catenin by another mechanism. Reduction of galectin-3 led to reduced nuclear B-catenin with a concomitant decrease in TCF4 transcriptional activity and expression of its target genes. Conversely, transfection of galectin-3 cDNA into colon cancer cells increased B-catenin expression and TCF4 transcriptional activity. Down-regulation of galectin-3 resulted in AKT and glycogen synthase kinase-3B (GSK-3B) dephosphorylation and increased GSK activity, increasing B-catenin phosphorylation and degradation. Ly294002, an inhibitor of phosphatidylinositol 3-kinase, and dominant-negative AKT, suppressed TCF4 transcriptional activity induced by galectin-3 whereas LiCl, a GSK-3B inhibitor, increased TCF4 activity, mimicking the effects of galectin-3. These results suggest that galectin-3 mediates Wnt signaling, at least in part, by regulating GSK-3B phosphorylation and activity via the phosphatidylinositol 3-kinase/AKT pathway, and, thus, the degradation of B-catenin in colon cancer cells. [Cancer Res 2009;69(4):1343-9]

Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells

“…Our data suggest that galectin-3 directly binds to EGFR to sequestrate it in the cytoplasm and prevents its nuclear shuttling but other (s) mechanism(s) are not excluded. Finally, we showed, in agreement with previous data (Song et al, 2009), that cyclin D1 is upregulated in galectin-3-expressing cells and that its levels are correlated with total MUC1 CT levels as recently described (Bitler et al, 2010). Cyclin-D1 upregulation in Sc control cells may contribute to their higher proliferative rate in vitro.…”

“…As MUC1 CT and galectin-3 in the nucleus promote cyclin-D1 expression through the accumulation and/ or stabilization of nuclear b-catenin, respectively (Wen et al, 2003;Song et al, 2009), we studied the levels of cyclin D1 in total cell lysates before and after a 10-min EGF treatment (Figure 4c). Our results show that Sc cells expressed higher levels of cyclin D1 than Sh1 cells in absence or in presence of EGF.…”

Intranuclear accumulation of galectin-3 is associated with a poor prognosis in patients with invasive intraductal papillary mucinous neoplasm

“…Galectin-3 contains a consensus sequence of GSK-3β phosphorylation. Nuclear importexport of galectin-3 has been reported to be dependent on this phosphorylation by GSK3β 32) . Galectin-3 has also been reported to be an important partner for the inactive form of GSK-3β to drive oncogenic transformation 33) .…”

The glycomic profile of invasive ductal carcinoma of the breast is altered in patients with hypoxic regions: implications for tumor behavior

“…On the other hand, decreased expression of cytoplasmatic Gal-3 is also associated with progression of human breast cancer [36,37]. Furthermore, Gal-3 plays an important role in the regulation of Wnt/b-catenin signaling --a key pathway in development, tissue homeostasis, and tumor growth [38].…”