title: Glucose-deprivation increases thyroid cancer cells sensitivity to metformin.
abstract: 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.
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Bikas
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Aneeta
authors.initials: A
authors.lastname: Patel
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: John
authors.initials: J
authors.lastname: Costello
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: McDaniel
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Klubo-Gwiezdzinska
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Olexander
authors.initials: O
authors.lastname: Larin
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoperia
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Burman
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Boyle
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Wartofsky
authors.affiliation: Division of EndocrinologyDepartment of Medicine, Medstar Washington Hospital Center, 110 Irving Street Northwest, Washington, District of Columbia 20010, USADepartment of PediatricsUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USABiomedical Instrumental CenterUniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4712, USACenter for Endocrine SurgeryKiev, UkraineDepartment of SurgeryMedstar Georgetown University Hospital, 3800 Reservoir Road, Washington, District of Columbia 20007, USA vasyl.vasko.ctr@usuhs.edu.
authors.forename: Vasyl
authors.initials: V
authors.lastname: Vasko
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D018263:Adenocarcinoma, Follicular / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008687:Metformin / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013963:Thyroid Hormones / Q000096:biosynthesis / Q000235:genetics; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D055372:AMP-Activated Protein Kinases; D002352:Carrier Proteins; D020169:Caspases; D003470:Culture Media; D003847:Deoxyglucose; D000091342:Endoplasmic Reticulum Chaperone BiP; D005947:Glucose; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D008687:Metformin; D009363:Neoplasm Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins
keywords: cell signaling; glucose; metformin; oncosis; thyroid cancer