Inhibition of lactate export suppresses growth and metabolism of anaplastic thyroid cancer
Bixiao Zhao, Keya Aggarwal, Abha Viswanathan, Matthew Nehs
Surgery, Brigham and Women"s Hospital, Boston, Massachusetts, United States
Objective: Anaplastic thyroid cancer (ATC) is an aggressive malignancy without effective treatments. ATC cells demonstrate upregulated glycolysis through the Warburg effect, generating lactate that is subsequently exported via the monocarboxylate transporter 4 (MCT4) protein. This study aims to determine if the MCT4 inhibitor acriflavine (ACF) can suppress ATC growth. Design: ATC cell lines 8505C and JL30 were grown in medium containing either low (3 mM) (LG) or high (25 mM) (HG) glucose concentration and 10 μM of ACF. Lactate levels in media and cell proliferation rates were measured using standard assays. Seahorse analysis using 8505C cells was performed to determine the extracellular acidification rate (ECAR) and glycolytic response to mitochondrial inhibitors. Setting: Research laboratory. Participants: None. Interventions: LG, HG, and ACF. Main Outcome Measures: Cell proliferation rate. Results: In the LG versus HG setting, lactate secretion was decreased by 30% for 8505C (P = 0.004) and 21% for JL30 (P = 0.002), while cell proliferation was reduced by 36% (P = 0.002) and 19% (P = 0.001), respectively. Addition of ACF to LG further lowered lactate levels by 71% for 8505C (P < 10-5) and 65% for JL30 (P < 10-4) compared to HG. Similarly, proliferation rates were dramatically reduced by 84% (P < 10-4) and 91% (P < 10-5), respectively. Addition of oligomycin in the Seahorse assay increased ECAR by 84 mpH/min in HG versus only 10 mpH/min in LG containing ACF. Conclusions: Lactate is a byproduct of ATC glycolytic metabolism. Inhibition of lactate secretion using ACF 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 adjuvant strategy in the treatment of ATC.
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