Details:

Alternative Title:
Endocr Relat Cancer
Publisher's site:
http://dx.doi.org/10.1530/ERC-15-0402
Personal Author:
Bikas, Athanasios ; Jensen, Kirk ; Patel, Aneeta ; Costello, John ; McDaniel, Dennis ; ... More +
Bikas, Athanasios ; Jensen, Kirk ; Patel, Aneeta ; Costello, John ; McDaniel, Dennis ; Klubo-Gwiezdzinska, Joanna ; Larin, Olexander ; Hoperia, Victoria ; Burman, Kenneth D ; Boyle, Lisa ; Wartofsky, Leonard ; Vasko, Vasyl Less -
Description:
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.
Subject:
[+]
Adenocarcinoma, Follicular
AMP-Activated Protein Kinases
Apoptosis
Article
Carcinoma, Papillary
Carrier Proteins
Caspases
Cell Division
Cell Line, Tumor
Cell Signaling
Culture Media
Deoxyglucose
Drug Screening Assays, Antitumor
Drug Synergism
Endoplasmic Reticulum
Enzyme Activation
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glucose
Glycolysis
Heat-Shock Proteins
Humans
Membrane Potential, Mitochondrial
Membrane Proteins
Metformin
Molecular Targeted Therapy
Neoplasm Proteins
Oncosis
Phosphorylation
Protein Processing, Post-Translational
Thyroid Cancer
Thyroid Hormones
Thyroid Neoplasms
Metformin

Source:
Endocr Relat Cancer. 22(6):919-932.
Pubmed ID:
26362676
Pubmed Central ID:
PMC6084428
Document Type:
Journal Article
Funding:
U2G PS000658/PS/NCHHSTP CDC HHS/United States
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:92526aa5c89c28f89d8f164462fd8ff65e60c20322a0bdb47c94f38db8148971
File Type:

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