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

¹Department of Gastroenterology, Hepatology, and Nutrition, ²Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ³Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas

^* To whom correspondence should be addressed. E-mail: rbresali{at}mdanderson.org.

	Abstract

Wnt/-catenin signaling plays an essential role in colon carcinogenesis. Galectin-3, a -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/-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 full-length galectin-3 cDNA, and effects on -catenin levels, subcellular distribution, and Wnt signaling were determined. Galectin-3 levels correlated with -catenin levels in a variety of colon cancer cell lines. Down-regulation of galectin-3 resulted in decreased -catenin protein levels but no change in -catenin mRNA levels, suggesting that galectin-3 modulates -catenin by another mechanism. Reduction of galectin-3 led to reduced nuclear -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 -catenin expression and TCF4 transcriptional activity. Down-regulation of galectin-3 resulted in AKT and glycogen synthase kinase-3 (GSK-3) dephosphorylation and increased GSK activity, increasing -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-3 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-3 phosphorylation and activity via the phosphatidylinositol 3-kinase/AKT pathway, and, thus, the degradation of -catenin in colon cancer cells. [Cancer Res 2009;69(4):1343–9]

Key Words: Galectin-3, -catenin, TCF4, GSK-3 activity, PI3K/AKT pathway