Lomibuvir sensitizes radioiodine-resistant thyroid cancer cell lines to radioiodine treatment by targeting hTERT RNA-dependent polymerase activity.

Abstract

Radioactive iodine (RAI) is selectively used in the treatment of residual or recurrent differentiated thyroid cancer for over fifty years. However, radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the decreased sodium iodide symporter (NIS) activity. Patients with RAIR-DTC derive limited benefit from RAI therapy, necessitating the exploration of new treatment options. In the current study, we aimed to explore the mechanism underlying thyroid cancer dedifferentiation and to provide new targets for RAIR therapy. We established a RAIR thyroid cancer cell line which was verified by the colony formation ability under radioiodine-131 treatment at doses up to 100 µCi. As expected, higher expressions of cancer stem cell genes, SOX2, CD133, and OCT4 A were found in RAIR cells compared to non-RAIR cells. Correspondingly, the expression of iodine-handling genes such as NIS, TPO, and Pendrin were downregulated. Interestingly, we discovered that the RNA-dependent RNA polymerase (RdRP) activity of TERT was also upregulated in RAIR cells, evidenced by the upregulation of phosphorylated telomerase reverse transcriptase (TERT), BRG1 and CDK1. Moreover, miR-146b-5p, transcribed by TERT gene, was likewise upregulated. RdRP inhibitor lomibuvir treatment downregulated miR-146b-5p level in RAIR cells, resulting in the upregulation of NIS gene expression. Lomibuvir not only restored the expressions of TPO and NIS but also downregulated the elevated ALDH1A1 and CD133 in RAIR cells. Consequently, the uptake of radioiodine-131 was significantly enhanced in these RAIR cells. Taken together, our research identifies novel therapeutic targets and provides new insights into the management of RAIR-DTC.