Combined Vorinostat and Chloroquine Inhibit Sodium Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo

Purpose 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.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 identify an acidic dipeptide within the NIS C-terminus which mediates binding to the 2 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.ConclusionsNIS 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.<br/

maternally inherited, lateralized trait pond snails is a Lymnaea stagnalis Mating behaviour in References Subject collections http://rsbl.royalsocietypublishing.org/subscriptions go to

Lateralization of the brain has traditionally been considered a specialization that is confined to the vertebrates, but recent studies have revealed that a range of invertebrates also have a brain that is structurally asymmetric and/or each side performs a different set of functions. Here, we show that the precopulatory mating behaviour of the pond snail Lymnaea stagnalis is lateralized. We present evidence that the asymmetry of the behaviour corresponds to the sinistral or dextral shell coil, or chirality, of the snail, and is apparently also controlled by a maternal effect locus. As sinistral snails also tend to have mirror image brains, these findings suggest that the lateralized sexual behaviour of L. stagnalis is set up early in development, and is a direct consequence of the asymmetry of the entire body

Mating behaviour in Lymnaea stagnalis pond snails is a maternally inherited, lateralized trait

Lateralization of the brain has traditionally been considered a specialization that is confined to the vertebrates, but recent studies have revealed that a range of invertebrates also have a brain that is structurally asymmetric and/or each side performs a different set of functions. Here, we show that the precopulatory mating behaviour of the pond snail Lymnaea stagnalis is lateralized. We present evidence that the asymmetry of the behaviour corresponds to the sinistral or dextral shell coil, or chirality, of the snail, and is apparently also controlled by a maternal effect locus. As sinistral snails also tend to have mirror image brains, these findings suggest that the lateralized sexual behaviour of L. stagnalis is set up early in development, and is a direct consequence of the asymmetry of the entire body