Tunicamycin as a Novel Redifferentiation Agent in Radioiodine Therapy for Anaplastic Thyroid Cancer

• Main Authors: Yoon Ju Choi, Jae-Eon Lee, Hyun Dong Ji, Bo-Ra Lee, Sang Bong Lee, Kil Soo Kim, In-Kyu Lee, Jungwook Chin, Sung Jin Cho, Jaetae Lee, Sang-Woo Lee, Jeoung-Hee Ha, Yong Hyun Jeon
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: International Journal of Molecular Sciences
• Subjects: tunicamycin; sodium-iodide symporter; anaplastic thyroid cancer; redifferentiation; radioiodine therapy
• Online Access: https://www.mdpi.com/1422-0067/22/3/1077
• ISSN: 1661-6596; 1422-0067

The silencing of thyroid-related genes presents difficulties in radioiodine therapy for anaplastic thyroid cancers (ATCs). Tunicamycin (TM), an N-linked glycosylation inhibitor, is an anticancer drug. Herein, we investigated TM-induced restoration of responsiveness to radioiodine therapy in radioiodine refractory ATCs. ¹²⁵I uptake increased in TM-treated ATC cell lines, including BHT101 and CAL62, which was inhibited by KClO₄, a sodium-iodide symporter (NIS) inhibitor. TM upregulated the mRNA expression of iodide-handling genes and the protein expression of NIS. TM blocked pERK1/2 phosphorylation in both cell lines, but AKT (protein kinase B) phosphorylation was only observed in CAL62 cells. The downregulation of glucose transporter 1 protein was confirmed in TM-treated cells, with a significant reduction in ¹⁸F-fluorodeoxyglucose (FDG) uptake. A significant reduction in colony-forming ability and marked tumor growth inhibition were observed in the combination group. TM was revealed to possess a novel function as a redifferentiation inducer in ATC as it induces the restoration of iodide-handling gene expression and radioiodine avidity, thereby facilitating effective radioiodine therapy.