Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death
Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death
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DOI：
10.1182/blood-2012-06-438234
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发表时间：
2012-11-29
期刊：
影响因子：
20.3
通讯作者：
Baum, Linda G.
中科院分区：
文献类型：
--
作者：
Clark, Mary C.;Pang, Mabel;Baum, Linda G.
弥漫性大b细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，是一种侵袭性恶性肿瘤。半乳糖凝集素-3 （gal-3）是半乳糖凝集素家族中唯一抗凋亡的成员，在DLBCL中过度表达。虽然gal-3可以定位于细胞内，但gal-3由DLBCL细胞分泌，并以碳水化合物依赖的方式结合回细胞表面。在DLBCL细胞上，gal-3的主要反受体被鉴定为跨膜酪氨酸磷酸酶CD45。用多价聚糖抑制剂GCS-100从CD45中去除细胞表面的gal-3使DLBCL细胞对化疗药物敏感。gal-3与CD45结合调节酪氨酸磷酸酶活性用GCS-100从CD45上去除内源性细胞表面gal-3增加了磷酸酶活性，而添加外源性gal-3则降低了磷酸酶活性。此外，GCS-100去除gal-3后，DLBCL细胞对化疗药物的敏感性增加需要CD45磷酸酶活性。Gal-3与高度糖基化的CD45糖型亚群的结合受到C2GnT-1糖基转移酶的调节，这表明CD45的特异性糖基化对于调节Gal-3介导的信号传导很重要。这些数据确定了细胞表面gal-3和CD45在DLBCL存活中的新作用，并提出了使DLBCL细胞致敏死亡的新治疗靶点。（血液，2012;120(23):4635-4644）
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. (Blood. 2012; 120(23):4635-4644)