Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK.
Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Ferrara 44124, Italy.
Cell Chem Biol. 2022 Mar 17;29(3):502-516.e7. doi: 10.1016/j.chembiol.2021.07.016. Epub 2021 Sep 13.
The sodium iodide symporter (NIS) functions to transport iodide and is critical for successful radioiodide ablation of cancer cells. Approaches to bolster NIS function and diminish recurrence post-radioiodide therapy are impeded by oncogenic pathways that suppress NIS, as well as the inherent complexity of NIS regulation. Here, we utilize NIS in high-throughput drug screening and undertake rigorous evaluation of lead compounds to identify and target key processes underpinning NIS function. We find that multiple proteostasis pathways, including proteasomal degradation and autophagy, are central to the cellular processing of NIS. Utilizing inhibitors targeting distinct molecular processes, we pinpoint combinatorial drug strategies giving robust >5-fold increases in radioiodide uptake. We also reveal significant dysregulation of core proteostasis genes in human tumors, identifying a 13-gene risk score classifier as an independent predictor of recurrence in radioiodide-treated patients. We thus propose and discuss a model for targetable steps of intracellular processing of NIS function.
钠碘转运体（NIS）的功能是转运碘，对于成功进行放射性碘消融癌症细胞至关重要。然而，致癌途径会抑制 NIS，同时 NIS 的调节也非常复杂，这使得增强 NIS 功能和减少放射性碘治疗后复发的方法受到阻碍。在这里，我们利用 NIS 进行高通量药物筛选，并对先导化合物进行严格评估，以确定和靶向支持 NIS 功能的关键过程。我们发现，多种蛋白质稳态途径，包括蛋白酶体降解和自噬，是 NIS 细胞处理的核心。利用针对不同分子过程的抑制剂，我们确定了组合药物策略，可以使放射性碘摄取增加 5 倍以上。我们还揭示了人类肿瘤中核心蛋白质稳态基因的显著失调，确定了一个包含 13 个基因的风险评分分类器作为放射性碘治疗患者复发的独立预测因子。因此，我们提出并讨论了一个可靶向 NIS 功能细胞内处理步骤的模型。
