Effect of Lactate Export Inhibition on Anaplastic Thyroid Cancer Growth and Metabolism

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 mu mol/L; ACF), syrosingopine (100 mu mol/L; SYR), or AZD3965 (20 mu mol/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. (C) 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.