ETA2024 Poster Presentations Basic thyroid cancer research-1 (10 abstracts)
Dual agonism of sodium iodide symporter function in vivo
Katie Brookes 1 , Ling Zha 1 , Jana Kim 2 , Sarinya Wongsanit 1 , Benjamin Small 3 , Hannah Nieto 1 , Vinodh Kannappan 3 , Weiguang Wang 4 , Sissy Jhiang 5 , Matthew Ringel 5 , Moray Campbell 6 , Kavitha Sunassee 2 , Philip Blower 2 , Kristien Boelaert 7 , Vicki Smith 8 , Martin Read 8 & Christopher McCabe 9
1Institute of Metabolism and Systems Science (Imss), and Centre of Endocrinology, Diabetes and Metabolism (Cedam), University of Birmingham, Birmingham, United Kingdom; 2School of Biomedical Engineering & Imaging Sciences, King’s College London, London, United Kingdom; 3Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, United Kingdom; 4Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, United Kingdom; 5Division of Endocrinology, Diabetes, and Metabolism and Cancer Biology Program, The Ohio State University College of Medicine and Comprehensive Cancer Center, Ohio, United States; 6Division of Cancer Biology, Cedars Sinai Cancer, Los Angeles, United States; 7College of Medical and Dental Scienc, University of Birmingham, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; 8Institute of Metabolism and Systems Research, University of Birmingham, Institute of Metabolism and Systems Science (Imss), and Centre of Endocrinology, Diabetes and Metabolism (Cedam), University of Birmingham, Birmingham, Birmingham, United Kingdom; 9University of Birmingham, Institute of Metabolism and Systems Science (Imss), and Centre of Endocrinology, Diabetes and Metabolism (Cedam), University of Birmingham, Birmingham, United Kingdom
Objectives: New approaches are urgently needed to enhance radioiodide (RAI) ablation of aggressive and metastatic thyroid cancer. Our previous experiments revealed that valosin-containing protein inhibitors (VCPi), such as disulfiram, markedly increase sodium iodide symporter (NIS) activity to promote RAI uptake. Recently, disulfiram was reported to inhibit NPL4 activity – a critical VCP cofactor – via its copper bound diethyldithiocarbamate metabolite Cu(DDC)2. We hence hypothesised that disulfiram and its metabolites increase RAI uptake by interfering with ER-Associated Degradation (ERAD) via a VCP/NPL4 pathway, permitting more NIS protein to be trafficked to the plasma membrane. Here, our aim was to understand the mechanistic impact of Cu(DDC)2 on NIS function in thyroid cells, as well as to investigate the clinical relevance of Cu(DDC)2-gene interactions.
Methods : We utilised RNA-Seq to identify transcriptional pathways altered by Cu(DDC)2. Technetium-99m pertechnetate (99mTc) uptake after intravenous administration was used to evaluate NIS function in wild-type BALB/c mice. TCGA was appraised to investigate Cu(DDC)2-gene interactions with recurrence in RAI-treated papillary thyroid cancer (PTC).
Results: Cu(DDC)2 increased RAI uptake in a dose-dependent manner across multiple thyroid cancer cell lines (mean ~3.4-fold). Subsequent RNA-Seq analysis revealed potent transcriptional changes in 8505C cells treated with Cu(DDC)2, including dysregulation of 357 genes encoding transcription factors. TaqMan RTPCR confirmed induction of transcription factors with key roles in regulating NIS expression, such as PAX8 and CREM, in multiple thyroid cell lines and human primary thyrocytes. In support, Cu(DDC)2 was unable to induce NIS mRNA expression or 125I uptake when PAX8 was depleted in primary thyrocytes and thyroid cancer cells. Importantly, significant induction of thyroidal 99mTc-uptake (~30%;n = 7;5 mg/kg dose;P < 0.05) in wild-type BALB/c mice treated intravenously with Cu(DDC)2 was associated with increasing PAX8 (1.4-fold;P < 0.05) and CREM mRNA (1.6-fold;P < 0.01) expression. Surprisingly, Cu(DDC)2 retained activity in the absence of NPL4 but not VCP in thyroid cancer cells and primary thyrocytes. Thus, Cu(DDC)2 required functional VCP but not NPL4 expression to enhance RAI uptake. We further appraised TCGA with LASSO regression analysis identifying a 22-gene riskscore classifier based on Cu(DDC)2-associated transcription factors, which showed a significantly worse prognosis for high-risk RAI-treated PTC [Hazard Ratio (HR)=11.6;95%CI 5.8-23.31;P < 0.001;n = 256].
Conclusions: We have identified a new dual agonist of RAI uptake dependent on the distinct functionalities of PAX8 and VCP, with the potential to directly impact RAI therapy for patients with aggressive thyroid cancer. Our bioinformatic analyses validated the clinical relevance of Cu(DDC)2-associated genes in RAI-treated PTC, enabling construction of a risk score classifier for predicting recurrence.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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