Use of metformin in the treatment of thyroid cancer

二甲双胍在治疗甲状腺癌中的用途

• 批准号: 10011331
• 负责人: Joanna Klubo-Gwiezdzinska
• 金额: $ 52.26万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10011331
• 关键词: Antidiabetic Drugs; Antineoplastic Agents; Cancer Cell Growth; Cancer Model; Cell Death; Cell Line; Cells; Clinical; Colon Carcinoma; Confocal Microscopy; Data; Deoxyglucose; Down-Regulation; Enzymes; Epidemiology; Experimental Designs; FRAP1 gene; Genus Hippocampus; Glucose; Glycerol-3-Phosphate Dehydrogenase; Glycolysis; Glycolysis Inhibition; Growth; Heterogeneity; Hexokinase 2; Hour; Human; In Vitro; In complete remission; Incidence; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Metabolic; Metabolism; Metformin; Mitochondria; Modeling; Molecular; Normal tissue morphology; Oxidative Phosphorylation; Papillary thyroid carcinoma; Predisposition; Quantitative Reverse Transcriptase PCR; Role; Signal Transduction; Stress; Techniques; Thyroid Gland; Thyroidectomy; Time; Treatment outcome; Western Blotting; cancer cell; cancer therapy; cancer type; cell growth; diabetic patient; epidemiology study; glucose metabolism; improved; in vivo; molecular marker; mortality; mouse model; novel; overexpression; radioiodine therapy; response; tumor growth; tumor metabolism; tumor molecular fingerprint

Mitochondrial glycerophosphate dehydrogenase (MGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin in the liver. There are no data on the expression and role of MGPDH as a metformin target in cancer. In this study, we evaluated MGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism.Experimental Design: We analyzed MGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on MGPDH expression were determined by qRT-PCR and Western blot analysis. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and MGPDH expression in metastatic thyroid cancer mouse models. Results: We show for the first time that MGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that MGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro Metformin treatment is associated with downregulation of MGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro Cells characterized by high MGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth-inhibitory effects of metformin in vitro and in vivo Conclusions: Our study established MGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.

线粒体甘油磷酸脱氢酶（MGPDH）是连接氧化磷酸化（OXPHOS）和糖酵解的关键酶，也是肝脏中抗糖尿病药物二甲双胍的靶点。没有关于MGPDH作为二甲双胍靶点在癌症中的表达和作用的数据。在这项研究中，我们评估了MGPDH作为二甲双胍在甲状腺癌中的潜在靶点，并研究了其在甲状腺癌代谢中的作用。 设计图：我们通过免疫染色分析了253例甲状腺癌和正常组织中MGPDH的表达，并通过共聚焦显微镜检查了其在甲状腺癌衍生细胞系（FTC 133，BCPAP）中的表达和定位。通过qRT-PCR和Western印迹分析确定二甲双胍对MGPDH表达的影响。Seahorse分析仪用于评估二甲双胍对甲状腺癌细胞中OXPHOS和糖酵解的影响。我们分析了二甲双胍对转移性甲状腺癌小鼠模型中肿瘤生长和MGPDH表达的影响。 结果：我们首次发现MGPDH在甲状腺癌中的表达高于正常甲状腺组织。我们证明MGPDH调节体外人甲状腺癌细胞的生长和OXPHOS速率，二甲双胍治疗与体外甲状腺癌中MGPDH表达的下调和OXPHOS的抑制相关。以MGPDH高表达为特征的细胞对二甲双胍体外OXPHOS抑制作用和二甲双胍体外和体内生长抑制作用更敏感。 结论：我们的研究确定MGPDH是甲状腺癌生长和代谢的一种新的调节剂，二甲双胍可以有效地靶向它。