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

Overview

Journal Cancer Res

Specialty Oncology

Date 2009 Feb 5

PMID 19190323

Citations 88

Authors

Shumei Song

Nachman Mazurek

Chunming Liu

Yunjie Sun

Qing Qing Ding

Kaifeng Liu

Mien-Chie Hung

Robert S Bresalier

Affiliations

Soon will be listed here.

Abstract

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

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References

Nakahara S, Raz A . Regulation of cancer-related gene expression by galectin-3 and the molecular mechanism of its nuclear import pathway. Cancer Metastasis Rev. 2007; 26(3-4):605-10. PMC: 3613988. DOI: 10.1007/s10555-007-9095-6. View

Sparks A, Morin P, Vogelstein B, Kinzler K . Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998; 58(6):1130-4. View

Yoshii T, Inohara H, Takenaka Y, Honjo Y, Akahani S, Nomura T . Galectin-3 maintains the transformed phenotype of thyroid papillary carcinoma cells. Int J Oncol. 2001; 18(4):787-92. DOI: 10.3892/ijo.18.4.787. View

Shishodia S, Koul D, Aggarwal B . Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J Immunol. 2004; 173(3):2011-22. DOI: 10.4049/jimmunol.173.3.2011. View

Shtutman M, Zhurinsky J, Simcha I, Albanese C, DAmico M, Pestell R . The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A. 1999; 96(10):5522-7. PMC: 21892. DOI: 10.1073/pnas.96.10.5522. View

Bresalier R, Yan P, Byrd J, Lotan R, Raz A . Expression of the endogenous galactose-binding protein galectin-3 correlates with the malignant potential of tumors in the central nervous system. Cancer. 1997; 80(4):776-87. View

Li J, Mizukami Y, Zhang X, Jo W, Chung D . Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3beta. Gastroenterology. 2005; 128(7):1907-18. DOI: 10.1053/j.gastro.2005.02.067. View

Oka N, Nakahara S, Takenaka Y, Fukumori T, Hogan V, Kanayama H . Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells. Cancer Res. 2005; 65(17):7546-53. DOI: 10.1158/0008-5472.CAN-05-1197. View

He X, Yin T, Grindley J, Tian Q, Sato T, Tao W . PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet. 2007; 39(2):189-98. PMC: 4681524. DOI: 10.1038/ng1928. View

10.

Oloumi A, Syam S, Dedhar S . Modulation of Wnt3a-mediated nuclear beta-catenin accumulation and activation by integrin-linked kinase in mammalian cells. Oncogene. 2006; 25(59):7747-57. DOI: 10.1038/sj.onc.1209752. View

11.

Lu Z, Ghosh S, Wang Z, Hunter T . Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 2004; 4(6):499-515. DOI: 10.1016/s1535-6108(03)00304-0. View

12.

Shimura T, Takenaka Y, Tsutsumi S, Hogan V, Kikuchi A, Raz A . Galectin-3, a novel binding partner of beta-catenin. Cancer Res. 2004; 64(18):6363-7. DOI: 10.1158/0008-5472.CAN-04-1816. View

13.

Shi Y, He B, Kuchenbecker K, You L, Xu Z, Mikami I . Inhibition of Wnt-2 and galectin-3 synergistically destabilizes beta-catenin and induces apoptosis in human colorectal cancer cells. Int J Cancer. 2007; 121(6):1175-81. DOI: 10.1002/ijc.22848. View

14.

Lin H, Pestell R, Raz A, Kim H . Galectin-3 enhances cyclin D(1) promoter activity through SP1 and a cAMP-responsive element in human breast epithelial cells. Oncogene. 2002; 21(52):8001-10. DOI: 10.1038/sj.onc.1205820. View

15.

Crawford H, Fingleton B, Goss K, Rubinfeld B, Polakis P, Matrisian L . The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene. 1999; 18(18):2883-91. DOI: 10.1038/sj.onc.1202627. View

16.

Araki Y, Okamura S, Hussain S, Nagashima M, He P, Shiseki M . Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways. Cancer Res. 2003; 63(3):728-34. View

17.

Koh T, Bulitta C, Fleming J, Dockray G, Varro A, Wang T . Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. J Clin Invest. 2000; 106(4):533-9. PMC: 380254. DOI: 10.1172/JCI9476. View

18.

Kolligs F, Bommer G, Goke B . Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion. 2002; 66(3):131-44. DOI: 10.1159/000066755. View

19.

Weston C, Davis R . Signal transduction: signaling specificity- a complex affair. Science. 2001; 292(5526):2439-40. DOI: 10.1126/science.1063279. View

20.

Giles R, van Es J, Clevers H . Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003; 1653(1):1-24. DOI: 10.1016/s0304-419x(03)00005-2. View