钠葡萄糖转运蛋白 2 (SGLT2) 抑制剂 (iSGLT2) 是批准用于治疗 2 型糖尿病的药物。最近的研究表明 iSGLT2 抑制某些癌细胞的生长。然而，其机制仍有待完全阐明。通过定量实时 PCR 和方法在正常结肠 CCD 841 CoN 和 HCT 116、HT-29、SW480 和 LoVo 结直肠癌 (CRC) 细胞系中测定了 SGLT2 水平。蛋白质印迹。使用 CCK-8 检查 iSGLT2 卡格列净对细胞增殖的影响，并通过 XF HS Seahorse 生物分析仪和流式细胞术分析评估其对 CRC 细胞代谢和肿瘤发生的作用。进行瞬时基因沉默实验和蛋白质-蛋白质相互作用网络分析，以评估 CRC 细胞中的 SGLT2 分子靶标。数据显示，用 iSGLT2 (50 µM) 处理 72 小时可诱导细胞周期停滞 (p < 0.001)、葡萄糖受损和能量代谢 (p<0.001)，促进 HCT 116 和 HT-29 细胞中的细胞凋亡和 ER 应激流入自噬 (p<0.001)。这些细胞事件伴随着 Sirtuin 3 (SIRT3) 上调 (p<0.01)，SIRT3 瞬时沉默实验也支持这一点，导致 iSGLT2 对细胞代谢/能量改变和诱导程序性细胞死亡的影响减弱。还评估了二肽基肽酶 4 (DPP4) 作为 SGLT2 和 SIRT3 潜在共同靶点的鉴定和验证。这些结果加深了对 iSGLT2 在限制 CRC 肿瘤发生中的贡献的认识，揭示了细胞毒性机制中的 SGLT2/SIRT3 轴。© 2024。作者。

Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated.The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein-protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells.Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed.These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms.© 2024. The Author(s).