Pharmacological enhancement of radioiodine uptake using Src kinase inhibitors

Research output: Contribution to journalAbstract

Authors

  • Vikki Poole
  • Bhavika Modasia
  • Rebecca Thompson
  • Waraporn Imruetaicharoenchoke
  • Vicki Smith

Abstract

Background
Radioiodine imaging, cell ablation and treatment of metastases in thyroid cancer rely on the presence of a functional sodium iodide symporter (NIS) in the basolateral plasma membrane (PM) of thyrocytes. Augmenting NIS PM localisation represents an important therapeutic strategy for increasing radioiodine delivery. We previously described a mechanism by which NIS is internalised by pituitary tumor-transforming gene-binding factor (PBF) in thyroid cells, significantly reducing radioiodine uptake. Importantly, we demonstrated that PBF phosphorylation at Y174 by Src kinase mediated NIS repression, which could be rescued by the Src family kinase (SFK) inhibitor PP1. Methods
We have now replicated these findings in breast cancer cells, further elucidated the mechanism of repression and identified a more potent inhibitor of PBF-pY174.
Results In MCF-7 and MDA-MB-231 breast cancer cells with either exogenous or all-trans retinoic acid/dexamethasone-induced NIS expression, PBF significantly repressed radioiodine uptake and this was reversible with PP1 treatment. PBF-Y174 is also a critical part of an endocytosis motif and mutation results in PM accumulation. Mutation of a predicted Src consensus sequence (EEN170-172AAA) abrogated pY174 and radioiodine uptake repression, confirming Src-dependent Y174 phosphorylation and demonstrating that NIS repression is mediated by phospho-PBF and not PM-bound PBF. Treatment with the SFK inhibitor dasatinib potently inhibited PBF-pY174 and restored radioiodine uptake. In the presence of dasatinib-resistant Src (T341I), dasatinib no longer rescued PBF repression of NIS, indicating that Src and no other SFK mediates PBF phosphorylation.
Conclusions
Taken together, these data suggest that Src inhibition can effectively enhance radioiodine uptake in multiple tumour types, with implications for improving outcomes in thyroid cancer and utilising NIS for the treatment of other tumours.

Details

Original languageEnglish
Article numberO2
Pages (from-to)2
Number of pages1
JournalThyroid Research
Volume10(Suppl 1)
Issue number2
Publication statusPublished - 13 Feb 2017