RT Journal Article
SR Electronic
T1 Pharmacologically targeting a novel pathway of sodium iodide symporter trafficking to enhance radioiodine uptake
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 622241
DO 10.1101/622241
A1 Alice Fletcher
A1 Martin L. Read
A1 Caitlin E.M. Thornton
A1 Dean P. Larner
A1 Vikki L. Poole
A1 Katie Brookes
A1 Hannah R. Nieto
A1 Mohammed Alshahrani
A1 Rebecca J. Thompson
A1 Gareth G. Lavery
A1 Moray J. Campbell
A1 Kristien Boelaert
A1 Andrew S. Turnell
A1 Vicki E. Smith
A1 Christopher J. McCabe
YR 2019
UL http://biorxiv.org/content/early/2019/05/07/622241.abstract
AB Radioiodine treatment fails ≥25% of patients with thyroid cancer and has been proposed as a potential treatment for breast cancer. Cellular iodide uptake is governed by the sodium iodide symporter (NIS), which is frequently mislocalized in thyroid and breast tumours. However, the trafficking of NIS to the plasma membrane (PM) is ill-defined. Through mass spectrometry, co-immunoprecipitation, cell surface biotinylation and proximity ligation assays we identify two proteins which control NIS subcellular trafficking: ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP). HiLo microscopy revealed ARF4 enhanced NIS trafficking in co-incident PM vesicles, governed by a C-terminal VXPX motif, whilst papillary thyroid cancers (PTC) demonstrate repressed ARF4 expression. In contrast, VCP, the central protein in ER-associated degradation, specifically bound NIS and decreased its PM localization. Five chemically distinct allosteric VCP inhibitors all overcame VCP-mediated repression of NIS function. In mice, two re-purposed FDA-approved VCP inhibitors significantly enhanced radioiodine uptake into thyrocytes, whilst human primary thyrocytes showed similar increases. Critically, PTC patients with high tumoural VCP expression who received radioiodine had strikingly worse disease-free survival. These studies now delineate the mechanisms of NIS trafficking, and for the first time open the therapeutic possibility of systemically enhancing radioiodine uptake in patients via FDA-approved drugs.One Sentence Summary Novel NIS interactors ARF4 and VCP alter NIS trafficking in vitro, and FDA-approved VCP inhibitors can significantly enhance radioiodine uptake.