Glucose-deprivation increases thyroid cancer cells sensitivity to metformin.
Citation: Endocrine-Related Cancer. 22(6):919-32, 2015 Dec.PMID: 26362676Institution: MedStar Washington Hospital CenterDepartment: Medicine/EndocrinologyForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, U.S. Gov't, Non-P.H.S.Subject headings: *Adenocarcinoma, Follicular/pa [Pathology] | *Carcinoma, Papillary/pa [Pathology] | *Glucose/pd [Pharmacology] | *Metformin/pd [Pharmacology] | *Thyroid Neoplasms/pa [Pathology] | Adenocarcinoma, Follicular/me [Metabolism] | AMP-Activated Protein Kinases/me [Metabolism] | Apoptosis/de [Drug Effects] | Carcinoma, Papillary/me [Metabolism] | Carrier Proteins/bi [Biosynthesis] | Carrier Proteins/ge [Genetics] | Caspases/me [Metabolism] | Cell Division/de [Drug Effects] | Cell Line, Tumor | Culture Media/ch [Chemistry] | Culture Media/pd [Pharmacology] | Deoxyglucose/pd [Pharmacology] | Drug Screening Assays, Antitumor | Drug Synergism | Endoplasmic Reticulum/me [Metabolism] | Enzyme Activation/de [Drug Effects] | Gene Expression Profiling | Gene Expression Regulation, Neoplastic/de [Drug Effects] | Glycolysis/de [Drug Effects] | Glycolysis/ge [Genetics] | Heat-Shock Proteins/bi [Biosynthesis] | Heat-Shock Proteins/ge [Genetics] | Humans | Membrane Potential, Mitochondrial/de [Drug Effects] | Membrane Proteins/bi [Biosynthesis] | Membrane Proteins/ge [Genetics] | Molecular Targeted Therapy | Neoplasm Proteins/bi [Biosynthesis] | Neoplasm Proteins/ge [Genetics] | Phosphorylation/de [Drug Effects] | Protein Processing, Post-Translational/de [Drug Effects] | Thyroid Hormones/bi [Biosynthesis] | Thyroid Hormones/ge [Genetics] | Thyroid Neoplasms/me [Metabolism]Year: 2015ISSN:- 1351-0088
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Journal Article | MedStar Authors Catalog | Article | 26362676 | Available | 26362676 |
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.
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