TY - UNPB
T1 - Targeting non-canonical pathways as a strategy to modulate the NIS symporter
AU - Read, Martin
AU - Brookes, Katie
AU - Thornton, Caitlin
AU - Fletcher, Alice
AU - Nieto, Hannah
AU - Alshahrani, Mohammed
AU - Khan, Rashida
AU - Borges de Souza, Patricia
AU - Zha, Ling
AU - Webster, Jamie
AU - Alderwick, Luke
AU - Campbell, Moray
AU - Boelaert, Kristien
AU - Smith, Vicki
AU - McCabe, Christopher
PY - 2021/3/3
Y1 - 2021/3/3
N2 - 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 utilised NIS in high-throughput drug screening and undertook 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 riskscore classifier as an independent predictor of recurrence in radioiodide-treated patients. We thus propose and discuss a new model for targetable steps of intracellular processing of NIS function.
AB - 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 utilised NIS in high-throughput drug screening and undertook 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 riskscore classifier as an independent predictor of recurrence in radioiodide-treated patients. We thus propose and discuss a new model for targetable steps of intracellular processing of NIS function.
KW - NIS
KW - radioiodide
KW - thyroid cancer
KW - proteosome
KW - autophagy
KW - protein homeostasis
U2 - 10.2139/ssrn.3797274
DO - 10.2139/ssrn.3797274
M3 - Preprint
BT - Targeting non-canonical pathways as a strategy to modulate the NIS symporter
PB - SSRN
ER -