Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer and

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2018 Apr 26

PMID 29691295

Citations 71

Authors

Shilpa Thakur

Brianna Daley

Kelli Gaskins

Vasyl V Vasko

Myriem Boufraqech

Dhaval Patel

Carole Sourbier

Jeff Reece

Sheue-Yann Cheng

Electron Kebebew

Sunita Agarwal

Joanna Klubo-Gwiezdzinska

Affiliations

Soon will be listed here.

Abstract

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. 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. 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 Metformin treatment is associated with downregulation of MGPDH expression and inhibition of OXPHOS in thyroid cancer Cells characterized by high MGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin and growth-inhibitory effects of metformin and Our study established MGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin. .

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