ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Combined Vorinostat and Chloroquine Inhibit Sodium-Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 14 citations in OpenAlex.
- From bench to bedside: the evolving role of iodine in thyroid cancer management.Nature reviews. Endocrinology · 2026Review
- Microenvironmental Control of Thyroid Cancer Plasticity and Radioiodine Resistance.International journal of molecular sciences · 2026Review
- Disulfiram metabolite Cu(DDC)EBioMedicine · 2026Article
- AP2: an indispensable host factor in virus infection.Journal of virology · 2026Review
- Cell-state transitions and microenvironmental remodeling in thyroid cancer progression revealed by single-cell and spatial transcriptomics.Frontiers in immunology · 2026Review
- Targeting EZH2 reverses thyroid cell dedifferentiation and enhances iodide uptake in anaplastic thyroid cancer.FEBS letters · 2026Article
- Targeted NanoBiT Screening Identifies a Novel Interaction Between SNAPIN and Influenza A Virus M1 Protein.Biology · 2025Article
- Crosstalk between acetylation modification and autophagy in cancer: roles, mechanisms, and therapeutic potential.Cell death discovery · 2025Review
- Gadd45B Deficiency Drives Radio-Resistance in BRAFCancers · 2025Article
- Targeting Src tyrosine kinase to enhance radioiodide uptake in breast cancer.Endocrine-related cancer · 2025Article
- A calcium-sensing receptor dileucine motif directs internalization to spatially distinct endosomal signaling pathways.iScience · 2025Article
- A New Twist on a Classic: Enhancing Radioiodine Uptake in Advanced Thyroid Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Novel molecular typing reveals the risk of recurrence in patients with early-stage papillary thyroid cancer.Thyroid research · 2024Article
- Functional characterization of novel compound heterozygous missenseFrontiers in endocrinology · 2024Article
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20 authors at 5 institutions in 3 countries.
Funding
Abstract
purposePatients 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. EXPERIMENTAL
designInformed 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.
resultsWe identified an acidic dipeptide within the NIS C-terminus that mediates binding to the σ2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine (CQ) modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, CQ 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.
conclusionsNIS internalization 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. See related commentary by Lechner and Brent, p. 1220.
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