碘化钠转运体
伏立诺他
癌症研究
共转运蛋白
甲状腺癌
体内
药理学
内吞作用
甲状腺髓样癌
医学
癌症
化学
生物
细胞
内科学
组蛋白脱乙酰基酶
生物化学
生物技术
运输机
基因
组蛋白
作者
Martin Read,Katie Brookes,Ling Zha,Selvambigai Manivannan,Jana Kim,Merve Kocbiyik,Alice Fletcher,Caroline M Gorvin,George Firth,Gilbert O. Fruhwirth,Juan Pablo Nicola,Sissy Jhiang,Matthew D. Ringel,Moray J. Campbell,Kavitha Sunassee,Philip J. Blower,Kristien Boelaert,Hannah Nieto,Vicki E. Smith,Christopher J. McCabe
标识
DOI:10.1158/1078-0432.ccr-23-2043
摘要
Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo.Informed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells. Systemic drug responses were monitored via 99mTc pertechnetate gamma counting and gene expression in BALB/c mice.We identify an acidic dipeptide within the NIS C-terminus which mediates binding to the σ2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, chloroquine treatment of BALB/c mice significantly enhanced thyroidal uptake of 99mTc pertechnetate in combination with the histone deacetylase (HDAC) inhibitor vorinostat/ SAHA, accompanied by increased thyroidal NIS mRNA. Bioinformatic analyses validated the clinical relevance of AP2 genes with disease-free survival in RAI-treated DTC, enabling construction of an AP2 gene-related risk score classifier for predicting recurrence.NIS internalisation is specifically druggable in vivo. Our data therefore provide new translatable potential for improving RAI therapy using FDA-approved drugs in patients with aggressive thyroid cancer.
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