SGLT2 inhibition restrains thyroid cancer growth via G1/S phase transition arrest and apoptosis mediated by DNA damage response signaling pathways

作者：Yan Wang, Longyan Yang, Lin Mao, Lijie Zhang, Yingjun Zhu, Yongsong Xu, Yanan Cheng, Rongxin Sun, Yuanyuan Zhang, Jing Ke, Dong Zhao · 发表于：Cancer Cell International · 年份：2022 · DOI：10.1186/s12935-022-02496-z · 被引用次数：68 · 研究领域：Diabetes Treatment and Management、Neuroendocrine Tumor Research Advances、Pancreatic function and diabetes

BACKGROUND: Although the prognosis for most patients with papillary thyroid cancer (PTC) is good, the present treatment is ineffective for 5-10% patients. Several studies found sodium-glucose cotransporter 2 (SGLT2) inhibitors may inhibit the growth of tumors. However, whether SGLT2 inhibitors have therapeutic effect on thyroid cancer remains unclear. MATERIALS AND METHODS: The levels of SGLT2 in PTC and normal thyroid tissue were assessed by immunohistochemistry and clinical dataset analysis. Cell growth was detected by the CCK-8 and colony formation. Glucose uptake into thyroid cancer cell was evaluated by 2-DG uptake assay. Glycolysis were analyzed by Seahorse XF Extracellular Flux Analysis. RNA-seq were used to screen differentially expressed genes of cells treated with/without canagliflozin (a SGLT2 inhibitor). Furthermore, flow cytometry, western blot, and gene set enrichment analysis were employed to elucidate cell cycle, apoptosis and the underlying mechanism of the anticancer effect of canagliflozin. The effect of canagliflozin on thyroid cancer growth was further confirmed in vivo through xenograft formation assay. RESULTS: SGLT2 inhibition attenuated the growth of thyroid cancer cells in vitro and in vivo. Canagliflozin inhibited glucose uptake, glycolysis and AKT/mTOR signaling activation, and increased AMPK activation in thyroid cancer cell. Furthermore, canagliflozin inhibited G1/S phase transition and cyclin D1, cyclin D3, cyclin E1, cyclin E2, and E2F1 express...