TY - JOUR
T1 - Galectin-3 mediates nuclear β-catenin accumulation and wnt signaling in human colon cancer cells by regulation of glycogen synthase kinase-3β activity
AU - Song, Shumei
AU - Mazurek, Nachman
AU - Liu, Chunming
AU - Sun, Yunjie
AU - Ding, Qing Qing
AU - Liu, Kaifeng
AU - Hung, Mien Chie
AU - Bresalier, Robert S.
PY - 2009/2/15
Y1 - 2009/2/15
N2 - 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 tran-scriptional activity. Down-regulation of galectin-3 resulted in AKT and glycogen synthase kinase-3β (GSK-3β) dephosphor-ylation 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.
AB - 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 tran-scriptional activity. Down-regulation of galectin-3 resulted in AKT and glycogen synthase kinase-3β (GSK-3β) dephosphor-ylation 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=60549098654&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-4153
DO - 10.1158/0008-5472.CAN-08-4153
M3 - Article
C2 - 19190323
AN - SCOPUS:60549098654
SN - 0008-5472
VL - 69
SP - 1343
EP - 1349
JO - Cancer Research
JF - Cancer Research
IS - 4
ER -