Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, 565-0871, Japan.
Glycoconj J. 2010 Oct;27(7-9):649-59. doi: 10.1007/s10719-010-9310-5. Epub 2010 Oct 16.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many cancer cells but not in normal ones. Recombinant TRAIL and agonistic antibodies to its cognate receptors are currently being studied as promising anticancer drugs. However, preclinical and clinical studies have shown that many types of human cancers are resistant to TRAIL agonists. We previously reported that a deficiency of fucosylation, which is one of the most common oligosaccharide modifications, leads to resistance to TRAIL-induced apoptosis. In contrast, DNA methylation is associated with silencing of various tumor suppressor genes and resistance of cancer cells to anticancer drugs. The aim of this study is to clarify the involvement of DNA methylation in the regulation of cellular fucosylation and the susceptibility to TRAIL-induced apoptosis. When nineteen cancer cell lines with relatively low fucosylation levels were treated with a novel methyltransferase inhibitor, zebularine, an increase in the fucosylation level was observed in many cancer cell lines. The expression of fucosylation-related genes, such as the FX, GDP-fucose transporter, and Fut4 genes, was significantly increased after the treatment with zebularine. Moreover, a synergistic effect of zebularine on TRAIL-induced apoptosis was observed in several cancer cell lines, in which fucosylation was increased by treatment with zebularine. This synergistic effect was independent of the expression of TRAIL receptors and caspase-8. These results indicate that cellular fucosylation is regulated through DNA methylation in many cancer cells. Moreover, zebularine might be useful as a combination drug with TRAIL-based therapies in patients with TRAIL-resistant cancer.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导许多癌细胞凋亡，但对正常细胞则无此作用。目前，重组 TRAIL 和其同源受体的激动性抗体被作为有前途的抗癌药物进行研究。然而，临床前和临床研究表明，许多类型的人类癌症对 TRAIL 激动剂具有抗性。我们之前曾报道过，岩藻糖基化的缺乏（最常见的寡糖修饰之一）会导致对 TRAIL 诱导的细胞凋亡的抗性。相反，DNA 甲基化与各种肿瘤抑制基因的沉默以及癌细胞对抗癌药物的抗性有关。本研究旨在阐明 DNA 甲基化在调节细胞岩藻糖基化和 TRAIL 诱导的细胞凋亡敏感性中的作用。当用新型甲基转移酶抑制剂 zebularine 处理 19 种岩藻糖基化水平相对较低的癌细胞系时，许多癌细胞系的岩藻糖基化水平增加。zebularine 处理后，岩藻糖基化相关基因（如 FX、GDP-岩藻糖转运蛋白和 Fut4 基因）的表达显著增加。此外，在几种癌细胞系中观察到 zebularine 与 TRAIL 诱导的细胞凋亡的协同作用，其中通过 zebularine 处理增加了岩藻糖基化。这种协同作用与 TRAIL 受体和 caspase-8 的表达无关。这些结果表明，在许多癌细胞中，细胞岩藻糖基化是通过 DNA 甲基化来调节的。此外，zebularine 可能可作为 TRAIL 耐药癌症患者与 TRAIL 为基础的治疗相结合的药物。
