Galectin-3 Binds to CD45 on Diffuse Large B-cell Lymphoma Cells to Regulate Susceptibility to Cell Death

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2012 Oct 16

PMID 23065155

Citations 41

Authors

Mary C Clark

Mabel Pang

Daniel K Hsu

Fu-Tong Liu

Sven de Vos

Randy D Gascoyne

Jonathan Said

Linda G Baum

Affiliations

Soon will be listed here.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and an aggressive malignancy. Galectin-3 (gal-3), the only antiapoptotic member of the galectin family, is overexpressed in DLBCL. While gal-3 can localize to intracellular sites, gal-3 is secreted by DLBCL cells and binds back to the cell surface in a carbohydrate-dependent manner. The major counterreceptor for gal-3 on DLBCL cells was identified as the transmembrane tyrosine phosphatase CD45. Removal of cell-surface gal-3 from CD45 with the polyvalent glycan inhibitor GCS-100 rendered DLBCL cells susceptible to chemotherapeutic agents. Binding of gal-3 to CD45 modulated tyrosine phosphatase activity; removal of endogenous cell-surface gal-3 from CD45 with GCS-100 increased phosphatase activity, while addition of exogenous gal-3 reduced phosphatase activity. Moreover, the increased susceptibility of DLBCL cells to chemotherapeutic agents after removal of gal-3 by GCS-100 required CD45 phosphatase activity. Gal-3 binding to a subset of highly glycosylated CD45 glycoforms was regulated by the C2GnT-1 glycosyltransferase, indicating that specific glycosylation of CD45 is important for regulation of gal-3-mediated signaling. These data identify a novel role for cell-surface gal-3 and CD45 in DLBCL survival and suggest novel therapeutic targets to sensitize DLBCL cells to death.

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References

Stillman B, Hsu D, Pang M, Brewer C, Johnson P, Liu F . Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J Immunol. 2006; 176(2):778-89. DOI: 10.4049/jimmunol.176.2.778. View

Yang R, Hsu D, Liu F . Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci U S A. 1996; 93(13):6737-42. PMC: 39096. DOI: 10.1073/pnas.93.13.6737. View

Alizadeh A, Eisen M, Davis R, Ma C, Lossos I, Rosenwald A . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403(6769):503-11. DOI: 10.1038/35000501. View

Chen H, Zhou X, Yu G, Zhao Y, Ren Y, Zhou Y . Knockdown of core 1 beta 1, 3-galactosyltransferase prolongs skin allograft survival with induction of galectin-1 secretion and suppression of CD8+ T cells: T synthase knockdown effects on galectin-1 and CD8+ T cells. J Clin Immunol. 2012; 32(4):820-36. DOI: 10.1007/s10875-012-9653-8. View

Stel A, ten Cate B, Jacobs S, Kok J, Spierings D, Dondorff M . Fas receptor clustering and involvement of the death receptor pathway in rituximab-mediated apoptosis with concomitant sensitization of lymphoma B cells to fas-induced apoptosis. J Immunol. 2007; 178(4):2287-95. DOI: 10.4049/jimmunol.178.4.2287. View

Shipp M, Ross K, Tamayo P, Weng A, Kutok J, Aguiar R . Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med. 2002; 8(1):68-74. DOI: 10.1038/nm0102-68. View

Ahmad N, Gabius H, Andre S, Kaltner H, Sabesan S, Roy R . Galectin-3 precipitates as a pentamer with synthetic multivalent carbohydrates and forms heterogeneous cross-linked complexes. J Biol Chem. 2003; 279(12):10841-7. DOI: 10.1074/jbc.M312834200. View

OBrien S, Kay N . Maintenance therapy for B-chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2011; 9(1):22-31. View

Dumic J, Dabelic S, Flogel M . Galectin-3: an open-ended story. Biochim Biophys Acta. 2006; 1760(4):616-35. DOI: 10.1016/j.bbagen.2005.12.020. View

10.

Demotte N, Wieers G, Van Der Smissen P, Moser M, Schmidt C, Thielemans K . A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res. 2010; 70(19):7476-88. DOI: 10.1158/0008-5472.CAN-10-0761. View

11.

Cabrera P, Amano M, Mitoma J, Chan J, Said J, Fukuda M . Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death. Blood. 2006; 108(7):2399-406. PMC: 1895562. DOI: 10.1182/blood-2006-04-018556. View

12.

Streetly M, Maharaj L, Joel S, Schey S, Gribben J, Cotter F . GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood. 2010; 115(19):3939-48. PMC: 5292593. DOI: 10.1182/blood-2009-10-251660. View

13.

Xu Z, Weiss A . Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nat Immunol. 2002; 3(8):764-71. DOI: 10.1038/ni822. View

14.

Fulcher J, Chang M, Wang S, Almazan T, Hashimi S, Eriksson A . Galectin-1 co-clusters CD43/CD45 on dendritic cells and induces cell activation and migration through Syk and protein kinase C signaling. J Biol Chem. 2009; 284(39):26860-70. PMC: 2785374. DOI: 10.1074/jbc.M109.037507. View

15.

Lin C, Whang E, Donner D, Jiang X, Price B, Carothers A . Galectin-3 targeted therapy with a small molecule inhibitor activates apoptosis and enhances both chemosensitivity and radiosensitivity in papillary thyroid cancer. Mol Cancer Res. 2009; 7(10):1655-62. DOI: 10.1158/1541-7786.MCR-09-0274. View

16.

Marchetti M, Di Marco B, Cifone G, Migliorati G, Riccardi C . Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation. Blood. 2002; 101(2):585-93. DOI: 10.1182/blood-2002-06-1779. View

17.

Fukumori T, Kanayama H, Raz A . The role of galectin-3 in cancer drug resistance. Drug Resist Updat. 2007; 10(3):101-8. PMC: 3626271. DOI: 10.1016/j.drup.2007.04.001. View

18.

Muris J, Meijer C, Ossenkoppele G, Vos W, Oudejans J . Apoptosis resistance and response to chemotherapy in primary nodal diffuse large B-cell lymphoma. Hematol Oncol. 2006; 24(3):97-104. DOI: 10.1002/hon.774. View

19.

Zikherman J, Doan K, Parameswaran R, Raschke W, Weiss A . Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival. Proc Natl Acad Sci U S A. 2011; 109(1):E3-12. PMC: 3252956. DOI: 10.1073/pnas.1117374108. View

20.

Lepur A, Salomonsson E, Nilsson U, Leffler H . Ligand induced galectin-3 protein self-association. J Biol Chem. 2012; 287(26):21751-6. PMC: 3381137. DOI: 10.1074/jbc.C112.358002. View