Effect of transforming growth factor-β1 on functional expression of monocarboxylate transporter 1 in alveolar epithelial A549 cells

Abstract

Epithelial-mesenchymal transition (EMT) contributes to the development of severe lung diseases, such as pulmonary fibrosis. Recently, it has been reported that EMT involves complex metabolic reprogramming triggered by several factors including transforming growth factor (TGF-β1) and that monocarboxylate transporter (MCT1) plays an essential role in these metabolic changes. The aim of the present study was to clarify the functional expression of MCT1 during TGF-β1-induced EMT in alveolar epithelial A549 cells. The transport function of MCT1 in A549 cells was examined using [ 3 H]γ-hydroxybutyrate (GHB) and [ 3 H]lactic acid (LA) as substrates and α-cyano-4-hydroxycinnamate (CHC), lactic acid, phloretin, and AR-C155858 (AR) as inhibitors of MCT1. EMT was induced by treating the cells with TGF-β1. mRNA and protein expression levels were analyzed using real-time PCR and western blotting, respectively. Time-, temperature-, and pH-dependent GHB and LA uptake were observed in A549 cells. CHC, lactic acid, phloretin, and AR significantly inhibited the uptake of GHB in a concentration-dependent manner, suggesting that MCT1 is primarily responsible for transport of monocarboxylates such as GHB and LA in A549 cells. TGF-β1 treatment significantly enhanced GHB and LA uptake as well as the mRNA and protein expression levels of MCT1 in A549 cells. These changes were neutralized by co-treatment with SB431542, an inhibitor for the TGF-β1 signaling pathway.CHC and AR had no effect on TGF-β1-induced EMT-related gene expression changes.Here, we have clearly characterized functional expression of MCT1 in A549 cells and have shown that MCT1 may be upregulated via the TGF-β1 signaling pathway.

Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment

“…HIF-1α in turn increases glycolysis and increased lactate production ( Guido et al, 2012 ; Heinzelmann et al, 2018 ; Yoshida et al, 2019 ). In tumor cells, TGF-β upregulates MCT1, increasing their capacity to uptake metabolites like lactate ( Uddin et al, 2020 ).…”