KT5823 Differentially Modulates Sodium Iodide Symporter Expression, Activity, and Glycosylation between Thyroid and Breast Cancer Cells
KT5823 Differentially Modulates Sodium Iodide Symporter Expression, Activity, and Glycosylation between Thyroid and Breast Cancer Cells
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DOI：
10.1210/en.2010-0782
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发表时间：
2011-03-01
期刊：
影响因子：
4.8
通讯作者：
Jhiang, Sissy
中科院分区：
文献类型：
--
作者：
Beyer, Sasha;Lakshmanan, Aparna;Jhiang, Sissy
Na+/I-同向转运蛋白 (NIS) 介导的甲状腺滤泡细胞吸收碘是甲状腺癌放射性碘治疗的基础。 NIS 蛋白也在大多数乳腺肿瘤中表达，提高了乳腺癌放射性核素治疗的潜力。 KT5823 是一种星形孢菌素相关蛋白激酶抑制剂，已被证明可以增加促甲状腺激素诱导的 NIS 表达，从而增加甲状腺细胞中的碘化物吸收。在这项研究中，我们发现在反式视黄酸和氢化可的松处理的 MCF-7 乳腺癌细胞中，KT5823 在治疗 0.5 小时内不会增加但会减少碘化物的摄取。此外，KT5823 会积累低糖基化 NIS，这种效应在乳腺癌细胞中比甲状腺细胞中更为明显。低糖基化的 NIS 是核心糖基化的，尚未通过高尔基体加工，但能够运输到细胞表面。 KT5823 在 N 连接糖基化途径中类似于布雷菲德菌素 A 的调节点上阻碍复杂的 NIS 糖基化，而不是针对 NIS 的特定 N-糖基化位点。在其他乳腺癌细胞以及表达外源 NIS 的人胚胎肾细胞中也观察到 KT5823 介导的 NIS 活性和糖基化作用。总而言之，KT5823 将作为一种有价值的药理学试剂来揭示甲状腺癌细胞和乳腺癌细胞在多个水平上差异 NIS 调节的机制。 （内分泌学152：782-792，2011）
Na+/I-symporter (NIS)-mediated iodide uptake into thyroid follicular cells serves as the basis of radioiodine therapy for thyroid cancer. NIS protein is also expressed in the majority of breast tumors, raising potential for radionuclide therapy of breast cancer. KT5823, a staurosporine-related protein kinase inhibitor, has been shown to increase thyroid-stimulating hormone-induced NIS expression, and thus iodide uptake, in thyroid cells. In this study, we found that KT5823 does not increase but decreases iodide uptake within 0.5 h of treatment in trans-retinoic acid and hydrocortisone-treated MCF-7 breast cancer cells. Moreover, KT5823 accumulates hypoglycosylated NIS, and this effect is much more evident in breast cancer cells than thyroid cells. The hypoglycosylated NIS is core glycosylated, has not been processed through the Golgi apparatus, but is capable of trafficking to the cell surface. KT5823 impedes complex NIS glycosylation at a regulatory point similar to brefeldin A along the N-linked glycosylation pathway, rather than targeting a specific N-glycosylated site of NIS. KT5823-mediated effects on NIS activity and glycosylation are also observed in other breast cancer cells as well as human embryonic kidney cells expressing exogenous NIS. Taken together, KT5823 will serve as a valuable pharmacological reagent to uncover mechanisms underlying differential NIS regulation between thyroid and breast cancer cells at multiple levels. (Endocrinology 152: 782-792, 2011)