TY  - BOOK
AU  - Bikas, Athanasios
AU  - Burman, Kenneth D
AU  - Klubo-Gwiezdzinska, Joanna
AU  - Wartofsky, Leonard
TI  - Glucose-deprivation increases thyroid cancer cells sensitivity to metformin
SN  - 1351-0088
PY  - 2015///
KW  - *Adenocarcinoma, Follicular/pa [Pathology]
KW  - *Carcinoma, Papillary/pa [Pathology]
KW  - *Glucose/pd [Pharmacology]
KW  - *Metformin/pd [Pharmacology]
KW  - *Thyroid Neoplasms/pa [Pathology]
KW  - Adenocarcinoma, Follicular/me [Metabolism]
KW  - AMP-Activated Protein Kinases/me [Metabolism]
KW  - Apoptosis/de [Drug Effects]
KW  - Carcinoma, Papillary/me [Metabolism]
KW  - Carrier Proteins/bi [Biosynthesis]
KW  - Carrier Proteins/ge [Genetics]
KW  - Caspases/me [Metabolism]
KW  - Cell Division/de [Drug Effects]
KW  - Cell Line, Tumor
KW  - Culture Media/ch [Chemistry]
KW  - Culture Media/pd [Pharmacology]
KW  - Deoxyglucose/pd [Pharmacology]
KW  - Drug Screening Assays, Antitumor
KW  - Drug Synergism
KW  - Endoplasmic Reticulum/me [Metabolism]
KW  - Enzyme Activation/de [Drug Effects]
KW  - Gene Expression Profiling
KW  - Gene Expression Regulation, Neoplastic/de [Drug Effects]
KW  - Glycolysis/de [Drug Effects]
KW  - Glycolysis/ge [Genetics]
KW  - Heat-Shock Proteins/bi [Biosynthesis]
KW  - Heat-Shock Proteins/ge [Genetics]
KW  - Humans
KW  - Membrane Potential, Mitochondrial/de [Drug Effects]
KW  - Membrane Proteins/bi [Biosynthesis]
KW  - Membrane Proteins/ge [Genetics]
KW  - Molecular Targeted Therapy
KW  - Neoplasm Proteins/bi [Biosynthesis]
KW  - Neoplasm Proteins/ge [Genetics]
KW  - Phosphorylation/de [Drug Effects]
KW  - Protein Processing, Post-Translational/de [Drug Effects]
KW  - Thyroid Hormones/bi [Biosynthesis]
KW  - Thyroid Hormones/ge [Genetics]
KW  - Thyroid Neoplasms/me [Metabolism]
KW  - MedStar Washington Hospital Center
KW  - Medicine/Endocrinology
KW  - Journal Article
KW  - Research Support, U.S. Gov't, Non-P.H.S
N2  - 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
UR  - http://dx.doi.org/10.1530/ERC-15-0402
ER  -