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Updated: Sep 8, 2025
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
Effect of Lactate Export Inhibition on Anaplastic Thyroid Cancer Growth and Metabolism
Bixiao Zhao1, Abha Aggarwal1, Soo-Yeon Im2
1From the Department of Surgery (Zhao, Aggarwal, Viswanathan, Nehs), Brigham and Women's Hospital, Boston, MA.
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.
Insights
Inhibiting lactate shuttles in anaplastic thyroid cancer (ATC) cells significantly reduced their growth and energy production, especially in low glucose conditions. This suggests targeting these pathways could be a promising treatment strategy for aggressive ATC.
Area of Science:
- Oncology
- Cancer Metabolism
- Thyroid Cancer Research
Background:
- Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with limited effective treatment options.
- ATC cells exhibit increased glycolysis (Warburg effect), producing lactate exported by monocarboxylate transporter 4 (MCT4).
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting MCT4 and lactate transport in ATC.
- To determine if targeting lactate shuttles can suppress ATC cell proliferation and glycolytic capacity.
Main Methods:
- ATC cell lines were cultured in low (LG) or high (HG) glucose media.
- Cells were treated with lactate shuttle inhibitors: acriflavine (ACF), syrosingopine (SYR), or AZD3965 (AZD).
- Lactate levels, cell proliferation, and glycolytic response (Seahorse analysis) were measured.
Main Results:
- Inhibitors reduced lactate secretion and cell proliferation in ATC cell lines, particularly in LG conditions.
- ACF treatment in LG significantly decreased lactate secretion and proliferation compared to HG.
- Combined LG and AZD with ACF further diminished cell proliferation.
Conclusions:
- Inhibition of lactate shuttles effectively suppresses ATC cell proliferation and glycolytic capacity, especially in a low-glucose environment.
- Targeting glycolytic and lactate processing pathways presents a potential therapeutic strategy for anaplastic thyroid cancer.
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