Article ; Online: Effect of Lactate Export Inhibition on Anaplastic Thyroid Cancer Growth and Metabolism.
Journal of the American College of Surgeons
2022 Volume 234, Issue 6, Page(s) 1044–1050
Abstract: Background: Anaplastic thyroid cancer (ATC) is an aggressive malignancy without effective treatments. ATC cells demonstrate upregulated glycolysis (Warburg effect), generating lactate that is subsequently exported by monocarboxylate transporter 4 (MCT4). ...
Abstract | Background: Anaplastic thyroid cancer (ATC) is an aggressive malignancy without effective treatments. ATC cells demonstrate upregulated glycolysis (Warburg effect), generating lactate that is subsequently exported by monocarboxylate transporter 4 (MCT4). This study aims to determine whether MCT4 inhibition can suppress ATC growth. Study design: ATC cell lines 8505C, JL30, and TCO1 were grown in low (3 mmol/L; LG) or high (25 mmol/L; HG) glucose medium containing the lactate shuttle inhibitors acriflavine (10-25 μmol/L; ACF), syrosingopine (100 µmol/L; SYR), or AZD3965 (20 µmol/L; AZD). Lactate level and cell proliferation were measured with standard assays. Seahorse analysis was performed to determine glycolytic response. Results: Compared with HG, addition of ACF to LG decreased lactate secretion for both 8505C (p < 10-5) and JL30 (p < 10-4) cells, whereas proliferation was also reduced (p < 10-4 and 10-5, respectively). During Seahorse analysis, addition of oligomycin increased acidification by 84 mpH/min in HG vs 10 mpH/min in LG containing ACF (p < 10-5). Treatment with LG and SYR drastically diminished 8505C and TCO1 growth vs HG (p < 0.01 for both). LG and AZD treatment also led to reduced proliferation in tested cell lines (p ≤ 0.01 for all) that was further decreased by addition of ACF (p < 10-4 vs HG, p ≤ 0.01 vs LG and AZD). Conclusion: Inhibition of lactate shuttles significantly reduced proliferation and glycolytic capacity of ATC cells in a low-glucose environment. Targeting suppression of glycolytic and lactate processing pathways may represent an effective treatment strategy for ATC. |
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MeSH term(s) | Cell Line, Tumor ; Glucose/metabolism ; Humans ; Lactic Acid/metabolism ; Thyroid Carcinoma, Anaplastic/drug therapy ; Thyroid Carcinoma, Anaplastic/metabolism ; Thyroid Carcinoma, Anaplastic/pathology ; Thyroid Neoplasms/drug therapy ; Thyroid Neoplasms/pathology |
Chemical Substances | Lactic Acid (33X04XA5AT) ; Glucose (IY9XDZ35W2) |
Language | English |
Publishing date | 2022-04-11 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 1181115-8 |
ISSN | 1879-1190 ; 1072-7515 |
ISSN (online) | 1879-1190 |
ISSN | 1072-7515 |
DOI | 10.1097/XCS.0000000000000226 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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