Inhibition and Knockdown of Monocarboxylate Transporter 1 Induce L-Lactate Accumulation in T-Cell Acute Lymphoblastic Leukemia Cells

Abstract

Tumors exhibit the Warburg effect, characterized by elevated glucose metabolism through both oxidative phosphorylation and glycolysis to produce energy. To maintain intracellular pH and metabolic homeostasis, cancer cells depend on monocarboxylate transporters (MCTs) to export the glycolytic end product, l-lactate. Similar to other cancers, glucose metabolism is enhanced in T-cell acute lymphoblastic leukemia (T-ALL), supporting rapid cell proliferation. Although MCT1 expression and its sensitivity to inhibition have been reported in certain T-ALL models, the relative contributions of other co-expressed MCT isoforms (MCT2 and MCT4) to l-lactate transport are unclear. This study aimed to evaluate the functional contribution of MCT isoforms to l-lactate transport in human T-ALL cell lines. We examined the expression and function of MCTs in Jurkat E6-1 and MOLT-3 cells. RT-PCR and Western blot analyses confirmed mRNA and protein expression of MCT1, MCT2, and MCT4 in both cell lines. Treatment with AZD3965, an MCT1 and MCT2 inhibitor, significantly increased intracellular l-lactate levels in T-ALL cells. In contrast, selective inhibition of MCT2 with atorvastatin or MCT4 with AZD0095 and VB124 did not alter intracellular l-lactate levels. Consistent with these pharmacological findings, MCT1 knockdown using small interfering RNA led to significant intracellular l-lactate accumulation. Collectively, these findings indicate that MCT1 is the principal transporter responsible for l-lactate transport in T-ALL cell lines, despite the co-expression of MCT2 and MCT4. Of all the multiple co-expressed isoforms, MCT1 is the primary mediator of l-lactate transport and is a promising therapeutic target for T-ALL treatment.