Dual knockdown of Galectin-8 and its glycosylated ligand, the activated leukocyte cell adhesion molecule (ALCAM/CD166), synergistically delays in vivo breast cancer growth
Dual knockdown of Galectin-8 and its glycosylated ligand, the activated leukocyte cell adhesion molecule (ALCAM/CD166), synergistically delays in vivo breast cancer growth
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DOI：
10.1016/j.bbamcr.2019.03.010
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发表时间：
2019-08-01
影响因子：
5.1
通讯作者：
Elola, Maria T.
中科院分区：
文献类型：
--
作者：
Ferragut, Fatima;Cagnoni, Alejandro J.;Elola, Maria T.
半乳糖凝集素-8（Galectin-8，Gal-8），一种“串联重复”型半乳糖凝集素，已被描述为细胞功能的调节剂，包括粘附、扩散、生长停滞、凋亡、病原体识别、自噬和免疫调节。我们以前已经表明，激活的白细胞粘附分子（ALCAM），也称为CD 166，作为内源性Gal-8的受体。ALCAM是免疫球蛋白超家族的成员，其通过不同组织中的嗜同性（ALCAM-ALCAM）和嗜异性（即ALCAM-CD 6）相互作用参与细胞-细胞粘附。在这里，我们研究了ALCAM-Gal-8协会和糖基化依赖性机制，这些相互作用的生理相关性。我们发现，MDA-MB-231三阴性乳腺癌细胞中ALCAM的沉默以聚糖依赖性方式降低了细胞在Gal-8包被表面上的粘附和迁移。值得注意的是，Gal-8或ALCAM沉默也破坏了细胞-细胞粘附，并导致三阴性乳腺癌小鼠模型中肿瘤生长减少。此外，内源性ALCAM N-糖基化的结构表征显示了Gal-8结合的丰富的容许结构。重要的是，我们还发现细胞唾液酸化控制Gal-8介导的细胞粘附。总之，这些发现证明了ALCAM或Gal-8（或两者）在控制三阴性乳腺癌中的核心作用。
Galectin-8 (Gal-8), a 'tandem-repeat'-type galectin, has been described as a modulator of cellular functions including adhesion, spreading, growth arrest, apoptosis, pathogen recognition, autophagy, and immunomodulation. We have previously shown that activated leukocyte cell adhesion molecule (ALCAM), also known as CD166, serves as a receptor for endogenous Gal-8. ALCAM is a member of the immunoglobulin superfamily involved in cell-cell adhesion through homophilic (ALCAM-ALCAM) and heterophilic (i.e. ALCAM-CD6) interactions in different tissues. Here we investigated the physiologic relevance of ALCAM-Gal-8 association and glycosylation-dependent mechanisms governing these interactions. We found that silencing of ALCAM in MDA-MB-231 triple negative breast cancer cells decreases cell adhesion and migration onto Gal-8-coated surfaces in a glycan-dependent fashion. Remarkably, either Gal-8 or ALCAM silencing also disrupted cell-cell adhesion, and led to reduced tumor growth in a murine model of triple negative breast cancer. Moreover, structural characterization of endogenous ALCAM N-glycosylation showed abundant permissive structures for Gal-8 binding. Importantly, we also found that cell sialylation controls Gal-8-mediated cell adhesion. Altogether, these findings demonstrate a central role of either ALCAM or Gal-8 (or both) in controlling triple negative breast cancer.