Targeting novel sodium iodide symporter interactors ADP-ribosylation factor 4 and valosin-containing protein enhances radioiodine uptake Journal Article
| Authors: | Fletcher, A.; Read, M. L.; Thornton, C. E. M.; Larner, D. P.; Poole, V. L.; Brookes, K.; Nieto, H. R.; Alshahrani, M.; Thompson, R. J.; Lavery, G. G.; Landa, I.; Fagin, J. A.; Campbell, M. J.; Boelaert, K.; Turnell, A. S.; Smith, V. E.; McCabe, C. J. |
| Article Title: | Targeting novel sodium iodide symporter interactors ADP-ribosylation factor 4 and valosin-containing protein enhances radioiodine uptake |
| Abstract: | The sodium iodide symporter (NIS) is required for iodide uptake, which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer, where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined. Here, we used tandem mass spectrometry followed by coimmunoprecipitation and proximity ligation assays to identify and validate two key nodes—ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP)—controlling NIS trafficking. Using cell-surface biotinylation assays and highly inclined and laminated optical sheet microscopy, we demonstrated that ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP—a principal component of endoplasmic reticulum (ER)–associated degradation—governed NIS proteolysis. Gene expression analysis indicated VCP expression was particularly induced in aggressive thyroid cancers and in patients who had poorer outcomes following RAI treatment. Two repurposed FDA-approved VCP inhibitors abrogated VCP-mediated repression of NIS function, resulting in significantly increased NIS at the cell-surface and markedly increased RAI uptake in mouse and human thyroid models. Collectively, these discoveries delineate NIS trafficking and highlight the new possibility of systemically enhancing RAI therapy in patients using FDA-approved drugs. © 2020 American Association for Cancer Research. |
| Keywords: | controlled study; protein expression; treatment outcome; unclassified drug; human cell; nonhuman; drug targeting; protein function; protein motif; protein analysis; animal cell; mouse; gene expression; carboxy terminal sequence; protein degradation; small interfering rna; drug selectivity; endoplasmic reticulum; iodine 125; radioactive iodine; drug mechanism; drug uptake; immunoprecipitation; cell migration; tandem mass spectrometry; drug protein binding; protein modification; biotinylation; drug degradation; cell surface; sodium iodide symporter; astemizole; clotrimazole; ebastine; human; priority journal; article; hela cell line; breast cancer cell line; adenosine triphosphatase inhibitor; thyroid cancer cell line; mrna expression level; adenosine diphosphate ribosylation factor 4; eeyarestatin 1; nanosheet; nms 873; valosin containing protein; endoplasmic reticulum associated degradation; golgi membrane |
| Journal Title: | Cancer Research |
| Volume: | 80 |
| Issue: | 1 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-01-01 |
| Start Page: | 102 |
| End Page: | 115 |
| Language: | English |
| DOI: | 10.1158/0008-5472.Can-19-1957 |
| PUBMED: | 31672844 |
| PROVIDER: | scopus |
| PMCID: | PMC7470018 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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