Use of metformin in the treatment of thyroid cancer

二甲双胍在治疗甲状腺癌中的用途

基本信息

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
项目类别：
财政年份：
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

项目摘要

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标。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 作为二甲双胍治疗甲状腺癌的潜在靶点，并研究了它在甲状腺癌代谢中的贡献。实验设计：我们通过免疫染色分析了 253 例甲状腺癌和正常组织中的 MGPDH 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（FTC133、BCPAP）中的表达和定位。通过 qRT-PCR 和蛋白质印迹分析确定二甲双胍对 MGPDH 表达的影响。利用海马分析仪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：我们首次表明，与正常甲状腺相比，MGPDH 在甲状腺癌中过度表达。我们证明 MGPDH 在体外调节人甲状腺癌细胞的生长和 OXPHOS 率二甲双胍治疗与体外甲状腺癌中 MGPDH 表达的下调和 OXPHOS 的抑制有关以高 MGPDH 表达为特征的细胞对二甲双胍的 OXPHOS 抑制作用更敏感二甲双胍的体内外体外和生长抑制作用结论：我们的研究确定 MGPDH 是甲状腺癌生长和代谢的新型调节剂，二甲双胍可以有效地靶向该调节剂。