RESUMO
BACKGROUND: Although eukaryotic translation initiation factor 4E (eIF4E) is important in cancer development and progression, its role in thyroid cancer is not well understood. Ribavirin, an anti-viral drug, has been identified as an eIF4E inhibitor. Herein, we investigated the effects of ribavirin on thyroid cancer and its molecular mechanisms of action. MATERIALS AND METHODS: The effects of ribavirin on thyroid cancer was investigated using in vitro cellular assays and in vivo xenograft mouse model. The mechanism of its action on eIF4E-ß-catenin axis was examined using genetic and biochemical approaches. RESULTS: We show that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid cancer's response to paclitaxel. Mechanistically, ribavirin suppressed eIF4E phosphorylation and overexpression of its wildtype and phosphor-mimetic form (S209D) but not of the non-phosphorylatable form (S209A), which rescued the inhibitory effects of ribavirin in thyroid cancer cells. We further demonstrated that ribavirin suppressed phosphorylation and activities of ß-catenin and its subsequent gene transcriptional expression. ß-Catenin overexpression rescued the effects of ribavirin in thyroid cancer cells. Importantly, we show that eIF4E regulated ß-catenin and that the regulation depended on phosphorylation at S209. The in vivo inhibitory effects of ribavirin on phosphorylation of eIF4E and ß-catenin were also observed in thyroid tumor. CONCLUSIONS: Our data clearly demonstrate that ribavirin acts on thyroid cancer cells by inhibiting eIF4E/ß-catenin signaling. Our findings suggest that ribavirin has the potential to be repurposed for thyroid cancer treatment and also highlight the therapeutic value of inhibiting eIF4E-ß-catenin in thyroid cancer.
