VCP: A novel interactor of the sodium iodide symporter, which can be pharmacologically targeted to increase radioiodine uptake in human and mouse thyrocytes

By exploiting the sodium iodide symporter (NIS), ablative radioiodine
therapy is an effective treatment for papillary thyroid cancer (PTC).
Unfortunately, >25% of PTC patients are unable to accumulate therapeutically
sufficient radioiodine due to NIS dysregulation, and have
reduced mean survival times. Radioiodine therapy has been proposed
as a viable treatment for breast cancer but is hampered by
diminished membranous NIS. Currently, the regulation of NIS localisation
remains ill-defined.
Mass spectrometry, co-immunoprecipitation and proximity ligation assays
identified and validated VCP as a novel NIS interactor. VCP siRNAdepletion
increased radioiodine uptake in lentivirally-expressing-NIS breast
and thyroid cancer cells, and significantly boosted endogenous NIS function
in human thyrocytes. Conversely, VCP-overexpression repressed
radioiodine uptake, accompanied by lowered membranous NIS. Five VCP
inhibitors all overcame VCP inhibition of NIS function in our transformed
cells. Notably, FDA-approved VCP inhibitors Clotrimazole and Ebastine
augmented radioiodine uptake in mouse and human thyrocytes.
TCGA analyses revealed VCP mRNA expression is significantly upregulated
in PTC, providing a putative explanation for repressed NIS
function. High tumoral VCP expression is associated with a worse
disease-free survival when compared to low VCP expression. Strikingly,
in patients who receive radioiodine, high tumoral VCP expression
results in a markedly worse disease-free survival, indicating high
VCP expression correlates with a worse response to radioiodine
therapy.
Our data reveal a new pathway of NIS regulation. Critically, FDA-approved
VCP inhibitors highlight a novel potential therapeutic strategy
for enhancing radioiodine uptake in PTC patients while increasing
the feasibility of radioiodine therapy in breast cancer via
transient inhibition of VCP activity.