1. Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter
- Author
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Luke J. Alderwick, Christopher McCabe, Kristien Boelaert, Katie Brookes, Ling Zha, Martin L. Read, Jamie R.M. Webster, Alice Fletcher, Moray J. Campbell, Patricia Borges de Souza, Vicki Smith, Caitlin Thornton, Mohammed Alshahrani, Rashida Khan, and Hannah Nieto
- Subjects
Pharmacology ,Sodium-iodide symporter ,Symporters ,Clinical Biochemistry ,Autophagy ,Biological Transport ,Biology ,Biochemistry ,Proteostasis ,Proteasome ,Non canonical ,Neoplasms ,Drug Discovery ,Cancer cell ,Cancer research ,Humans ,Molecular Medicine ,Molecular Biology ,health care economics and organizations ,Function (biology) ,Intracellular - Abstract
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.
- Published
- 2022