Glucose-deprivation increases thyroid cancer cells sensitivity to metformin. 

 -  2015 
<br/><br/> Metformin inhibits thyroid cancer cell growth. We sought to determine if variable glucose concentrations in medium alter the anti-cancer efficacy of metformin. Thyroid cancer cells (FTC133 and BCPAP) were cultured in high-glucose (20 mM) and low-glucose (5 mM) medium before treatment with metformin. Cell viability and apoptosis assays were performed. Expression of glycolytic genes was examined by real-time PCR, western blot, and immunostaining. Metformin inhibited cellular proliferation in high-glucose medium and induced cell death in low-glucose medium. In low-, but not in high-glucose medium, metformin induced endoplasmic reticulum stress, autophagy, and oncosis. At micromolar concentrations, metformin induced phosphorylation of AMP-activated protein kinase and blocked p-pS6 in low-glucose medium. Metformin increased the rate of glucose consumption from the medium and prompted medium acidification. Medium supplementation with glucose reversed metformin-inducible morphological changes. Treatment with an inhibitor of glycolysis (2-deoxy-d-glucose (2-DG)) increased thyroid cancer cell sensitivity to metformin. The combination of 2-DG with metformin led to cell death. Thyroid cancer cell lines were characterized by over-expression of glycolytic genes, and metformin decreased the protein level of pyruvate kinase muscle 2 (PKM2). PKM2 expression was detected in recurrent thyroid cancer tissue samples. In conclusion, we have demonstrated that the glucose concentration in the cellular milieu is a factor modulating metformin's anti-cancer activity. These data suggest that the combination of metformin with inhibitors of glycolysis could represent a new strategy for the treatment of thyroid cancer. Copyright © 2015 Society for Endocrinology. 
<br/><br/><br/>English 
<br/><br/><label>ISSN: </label>1351-0088 
<br/><br/><label>Subjects--Topical Terms: </label><br/>*Adenocarcinoma, Follicular/pa [Pathology]<br/>*Carcinoma, Papillary/pa [Pathology]<br/>*Glucose/pd [Pharmacology]<br/>*Metformin/pd [Pharmacology]<br/>*Thyroid Neoplasms/pa [Pathology]<br/>Adenocarcinoma, Follicular/me [Metabolism]<br/>AMP-Activated Protein Kinases/me [Metabolism]<br/>Apoptosis/de [Drug Effects]<br/>Carcinoma, Papillary/me [Metabolism]<br/>Carrier Proteins/bi [Biosynthesis]<br/>Carrier Proteins/ge [Genetics]<br/>Caspases/me [Metabolism]<br/>Cell Division/de [Drug Effects]<br/>Cell Line, Tumor<br/>Culture Media/ch [Chemistry]<br/>Culture Media/pd [Pharmacology]<br/>Deoxyglucose/pd [Pharmacology]<br/>Drug Screening Assays, Antitumor<br/>Drug Synergism<br/>Endoplasmic Reticulum/me [Metabolism]<br/>Enzyme Activation/de [Drug Effects]<br/>Gene Expression Profiling<br/>Gene Expression Regulation, Neoplastic/de [Drug Effects]<br/>Glycolysis/de [Drug Effects]<br/>Glycolysis/ge [Genetics]<br/>Heat-Shock Proteins/bi [Biosynthesis]<br/>Heat-Shock Proteins/ge [Genetics]<br/>Humans<br/>Membrane Potential, Mitochondrial/de [Drug Effects]<br/>Membrane Proteins/bi [Biosynthesis]<br/>Membrane Proteins/ge [Genetics]<br/>Molecular Targeted Therapy<br/>Neoplasm Proteins/bi [Biosynthesis]<br/>Neoplasm Proteins/ge [Genetics]<br/>Phosphorylation/de [Drug Effects]<br/>Protein Processing, Post-Translational/de [Drug Effects]<br/>Thyroid Hormones/bi [Biosynthesis]<br/>Thyroid Hormones/ge [Genetics]<br/>Thyroid Neoplasms/me [Metabolism]
<br/><br/><label>Subjects--Geographic Terms: </label><br/>MedStar Washington Hospital Center
<br/><br/><label>Index Terms--Occupation: </label><br/>Medicine/Endocrinology
<br/><br/><label>Index Terms--Function: </label><br/>Journal Article<br/>Research Support, U.S. Gov't, Non-P.H.S.