Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death.
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.
Department of Pathology and Laboratory Medicine, University of California-Los Angeles School of Medicine, 10833 Le ConteAve,Los Angeles, CA 90095, USA.
Mary C
MC
Clark
Mabel
M
Pang
Daniel K
DK
Hsu
Fu-Tong
FT
Liu
Sven
S
de Vos
Randy D
RD
Gascoyne
Jonathan
J
Said
Linda G
LG
Baum
D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D037502:Galectin 3 / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D000069283:Rituximab; D046888:Tissue Array Analysis
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C505531:GCS-100; D037502:Galectin 3; D011134:Polysaccharides; D000069283:Rituximab; D005047:Etoposide; D003907:Dexamethasone; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase; D017493:Leukocyte Common Antigens