Valenzuela Hector F, Pace Karen E, Cabrera Paula V, White Rachel, Porvari Katja, Kaija Helena, Vihko Pirkko, Baum Linda G
Department of Pathology, School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1732, USA.
Cancer Res. 2007 Jul 1;67(13):6155-62. doi: 10.1158/0008-5472.CAN-05-4431.
Resistance to apoptosis is a critical feature of neoplastic cells. Galectin-1 is an endogenous carbohydrate-binding protein that induces death of leukemia and lymphoma cells, breast cancer cells, and the LNCaP prostate cancer cell line, but not other prostate cancer cell lines. To understand the mechanism of galectin-1 sensitivity of LNCaP cells compared with other prostate cancer cells, we characterized glycan ligands that are important for conferring galectin-1 sensitivity in these cells, and analyzed expression of glycosyltransferase genes in galectin-1-sensitive, prostate-specific antigen-positive (PSA(+)) LNCaP cells compared with a galectin-1-resistant PSA(-) LNCaP subclone. We identified one glycosyltransferase, core 2 N-acetylglucosaminyltransferase, which is down-regulated in galectin-1-resistant PSA(-) LNCaP cells compared with galectin-1-sensitive PSA(+) LNCaP cells. Intriguingly, this is the same glycosyltransferase required for galectin-1 susceptibility of T lymphoma cells, indicating that similar O-glycan ligands on different polypeptide backbones may be common death trigger receptors recognized by galectin-1 on different types of cancer cells. Blocking O-glycan elongation by expressing alpha2,3-sialyltransferase 1 rendered LNCaP cells resistant to galectin-1, showing that specific O-glycans are critical for galectin-1 susceptibility. Loss of galectin-1 susceptibility and synthesis of endogenous galectin-1 has been proposed to promote tumor evasion of immune attack; we found that galectin-1-expressing prostate cancer cells killed bound T cells, whereas LNCaP cells that do not express galectin-1 did not kill T cells. Resistance to galectin-1-induced apoptosis may directly contribute to the survival of prostate cancer cells as well as promote immune evasion by the tumor.
对凋亡的抵抗是肿瘤细胞的一个关键特征。半乳糖凝集素-1是一种内源性碳水化合物结合蛋白，可诱导白血病和淋巴瘤细胞、乳腺癌细胞以及LNCaP前列腺癌细胞系死亡，但对其他前列腺癌细胞系无效。为了理解与其他前列腺癌细胞相比，LNCaP细胞对半乳糖凝集素-1敏感的机制，我们鉴定了对赋予这些细胞半乳糖凝集素-1敏感性很重要的聚糖配体，并分析了半乳糖凝集素-1敏感的、前列腺特异性抗原阳性（PSA(+)）的LNCaP细胞与对半乳糖凝集素-1耐药的PSA(-) LNCaP亚克隆相比的糖基转移酶基因表达。我们鉴定出一种糖基转移酶，核心2 N-乙酰葡糖胺基转移酶，与对半乳糖凝集素-1敏感的PSA(+) LNCaP细胞相比，它在对半乳糖凝集素-1耐药的PSA(-) LNCaP细胞中表达下调。有趣的是，这与T淋巴瘤细胞对半乳糖凝集素-1敏感性所需的糖基转移酶相同，表明不同多肽主链上相似的O-聚糖配体可能是不同类型癌细胞上半乳糖凝集素-1识别的常见死亡触发受体。通过表达α2,3-唾液酸转移酶1阻断O-聚糖延长使LNCaP细胞对半乳糖凝集素-1产生耐药性，表明特定的O-聚糖对半乳糖凝集素-1敏感性至关重要。有人提出，对半乳糖凝集素-1敏感性的丧失和内源性半乳糖凝集素-1的合成可促进肿瘤逃避免疫攻击；我们发现表达半乳糖凝集素-1的前列腺癌细胞可杀死结合的T细胞，而不表达半乳糖凝集素-1的LNCaP细胞则不能杀死T细胞。对半乳糖凝集素-1诱导的凋亡的抵抗可能直接有助于前列腺癌细胞的存活，并促进肿瘤的免疫逃避。
