Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells
Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells
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DOI：
10.1158/0008-5472.can-07-6389
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发表时间：
2008-05-15
期刊：
影响因子：
11.2
通讯作者：
Lawrence, Theodore S.
中科院分区：
文献类型：
--
作者：
Contessa, Joseph N.;Bhojani, Mahaveer S.;Lawrence, Theodore S.
受体酪氨酸激酶（RTK）是治疗恶性肿瘤的治疗靶点。然而，肿瘤细胞通过并行信号级联的激活对靶向治疗产生耐药性。最近的证据表明，导致耐药性的冗余或补偿性生存信号是由细胞共表达的非靶向糖蛋白 RTK 启动的。我们假设破坏分泌途径翻译后机制的特定功能将是针对主要和冗余 RTK 信号传导的有效策略。使用 N 连接糖基化抑制剂衣霉素，我们发现几种 RTKS（EGFR、ErbB2、ErbB3 和 IGF-IR）的表达水平对 N 连接糖基化的抑制非常敏感。破坏这种合成过程会通过将受体保留在内质网/高尔基体区室中来降低肿瘤细胞中的细胞蛋白水平和受体活性。使用 U251 神经胶质瘤和 BXPC3 胰腺腺癌细胞系（两种对表皮生长因子受体靶向治疗具有抗性的细胞系），我们发现抑制 N 连接糖基化可显着减少通过 Akt 的 RTK 信号传导并使肿瘤细胞放射增敏。相比之下，在非转化细胞中进行的实验既没有显示 RTK 依赖性信号传导的减少，也没有显示放射敏感性的增强，这表明肿瘤和正常组织之间存在治疗比例的潜力。这项研究提供了证据，证明调节 N-连接糖基化的酶步骤是开发使肿瘤细胞对细胞毒性疗法敏感的方法的新靶点。
Receptor tyrosine kinases (RTK) are therapeutic targets for the treatment of malignancy. However, tumor cells develop resistance to targeted therapies through the activation of parallel signaling cascades. Recent evidence has shown that redundant or compensatory survival signals responsible for resistance are initiated by nontargeted glycoprotein RTKs coexpressed by the cell. We hypothesized that disrupting specific functions of the posttranslational machinery of the secretory pathway would be an effective strategy to target both primary and redundant RTK signaling. Using the N-linked glycosylation inhibitor, tunicamycin, we show that expression levels of several RTKS (EGFR, ErbB2, ErbB3, and IGF-IR) are exquisitely sensitive to inhibition of N-linked glycosylation. Disrupting this synthetic process reduces both cellular protein levels and receptor activity in tumor cells through retention of the receptors in the endoplasmic reticulum/Golgi compartments. Using U251 glioma and BXPC3 pancreatic adenocarcinoma cell lines, two cell lines resistant to epidermal growth factor receptor-targeted therapies, we show that inhibiting N-linked glycosylation markedly reduces RTK signaling through Akt and radiosensitizes tumor cells. In comparison, experiments in nontransformed cells showed neither a reduction in RTK-dependent signaling nor an enhancement in radiosensitivity, suggesting the potential for a therapeutic ratio between tumors and normal tissues. This study provides evidence that enzymatic steps regulating N-linked glycosylation are novel targets for developing approaches to sensitize tumor cells to cytotoxic therapies.