Selective Antitumor Activity of Datelliptium toward Medullary Thyroid Carcinoma by Downregulating RET Transcriptional Activity

SIMPLE SUMMARY: Medullary thyroid carcinoma (MTC) is a rare aggressive type of thyroid cancer with a propensity for metastasizing to the lymph nodes, liver, bones, and lungs. Previous studies have demonstrated that activated REarranged during Transfection (RET) mutants are key regulators of invasive and metastatic behaviors in MTC. The present study aimed to evaluate the antiinvasive and antimetastatic potential of a novel RET transcription inhibitor, datelliptium, which stabilizes the RET G-quadruplex structures and suppresses RET oncogene transcription by examining its effects on epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), and MTC cell migration. Interestingly, the ablation of RET with datelliptium resulted in decreased EMT, spheroid formation, and MTC cell migration. In this study, we also demonstrated the in vivo antitumor activity in TT tumor-bearing mice with about 75% tumor growth inhibition. ABSTRACT: Medullary thyroid carcinoma (MTC) is a rare aggressive form of thyroid cancer with high rates of metastasis. Sporadic and hereditary MTC are strongly driven by somatic and germline mutations, respectively, in the transmembrane REarranged during Transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase. Our previous study identified datelliptium as a novel RET transcription inhibitor, which stabilizes the RET G-quadruplex structures and suppresses RET oncogene transcription. The present study aimed to elucidate the effect of datelliptium on the suppression of epithelial-to-mesenchymal transition (EMT) and metastasis-related behaviors of MTC cells, including cell migration and formation of cancer stem cells (CSCs). Our results demonstrated that datelliptium downregulated the expression of the mesenchymal markers, including N-cadherin, vimentin, slug, snail, and claudin-1. Compared to untreated cells, datelliptium significantly decreased the migration of TT cells in a dose-dependent manner in a wound healing assay. Additionally, datelliptium significantly reduced the size of preformed spheroids from TT cells over the time course. Finally, datelliptium inhibited approximately 75% of MTC xenograft growth with minimal systemic toxicity. In conclusion, datelliptium exerts its antitumor activity against MTC cells by reducing the EMT program, migratory ability, and self-renewal capacity of TT cells, thus preventing invasive and metastatic behavior of MTC.