Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter.

Autor:	Read ML; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Brookes K; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Thornton CEM; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Fletcher A; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Nieto HR; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Alshahrani M; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Khan R; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Borges de Souza P; Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Ferrara 44124, Italy., Zha L; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., Webster JRM; Protein Expression Facility, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK., Alderwick LJ; Birmingham Drug Discovery Facility, School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK., Campbell MJ; Division of Pharmaceutics and Pharmacology, The Ohio State University, College of Pharmacy, Columbus, OH 43210, USA., Boelaert K; Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, UK., Smith VE; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK., McCabe CJ; Institute of Metabolism and Systems Research (IMSR), and Centre of Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK. Electronic address: mccabcjz@bham.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2022 Mar 17; Vol. 29 (3), pp. 502-516.e7. Date of Electronic Publication: 2021 Sep 13.
DOI:	10.1016/j.chembiol.2021.07.016
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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