Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo.
Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo.
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DOI：
10.1158/1078-0432.ccr-17-3167
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发表时间：
2018-08-15
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影响因子：
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通讯作者：
Klubo-Gwiezdzinska J
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文献类型：
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作者：
Thakur S;Daley B;Gaskins K;Vasko VV;Boufraqech M;Patel D;Sourbier C;Reece J;Cheng SY;Kebebew E;Agarwal S;Klubo-Gwiezdzinska J
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，也是抗糖尿病药物二甲双胍(MF)在肝脏中的靶点。目前还没有关于mGPDH作为二甲双胍靶标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作用。我们用免疫组织化学方法分析了253例甲状腺癌组织和正常组织中mGPDH的表达，并用共聚焦显微镜检测了mGPDH在甲状腺癌衍生细胞系FTC133、bCPAP中的表达和定位。用定量RT-PCR和免疫印迹法检测二甲双胍对mGPDH表达的影响。用海马分析仪检测二甲双胍对甲状腺癌细胞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肿瘤生长和mGPDH表达的影响。我们首次发现与正常甲状腺相比，mGPDH在甲状腺癌中过表达。我们证明了mGPDH在体外调节人甲状腺癌细胞的生长和OXPHOS率。在体外，二甲双胍治疗与下调mGPDH的表达和抑制OXPHOS的表达有关。MGPDH高表达的细胞在体外对二甲双胍的OXPHOS抑制作用和在体内外的生长抑制作用更敏感。我们的研究确定mGPDH是一种新的甲状腺癌生长和代谢调节因子，可以有效地被二甲双胍靶向。
Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) 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. 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. 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. 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. Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.