Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo. Clin Cancer Res 2018 Aug 15;24(16):4030-4043
Date
04/25/2018Pubmed ID
29691295Pubmed Central ID
PMC6095745DOI
10.1158/1078-0432.CCR-17-3167Scopus ID
2-s2.0-85051752165 (requires institutional sign-in at Scopus site) 127 CitationsAbstract
Purpose: 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 vivoConclusions: Our study established MGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin. Clin Cancer Res; 24(16); 4030-43. ©2018 AACR.
Author List
Thakur S, Daley B, Gaskins K, Vasko VV, Boufraqech M, Patel D, Sourbier C, Reece J, Cheng SY, Kebebew E, Agarwal S, Klubo-Gwiezdzinska JMESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Cell Proliferation
Glycerolphosphate Dehydrogenase
Glycolysis
Heterografts
Humans
Metformin
Mice
Mitochondria
Oxidative Phosphorylation
Thyroid Neoplasms
