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

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

Requests for reprints: Robert S. Bresalier, Department of Gastroenterology, Hepatology, and Nutrition, Unit 1466, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009. Phone: 713-745-4340; Fax: 713-745-9295; E-mail: rbresali{at}mdanderson.org.

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

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