Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells

Abstract

Dysregulation of glucose/lactate dynamics plays a role in cancer progression, and MCTs are key elements in metabolic remodeling. VEGF is a relevant growth factor in the maintenance of bone marrow microenvironment and it is also important in hematological diseases.Our aim was to investigate the role of VEGF in the metabolic adaptation of Acute myeloid leukemia (AML) cells by evaluating the metabolic profiles and cell features according to the AML lineage and testing lactate as a metabolic coin.Our in vitro results showed that AML promyelocytic (HL60) and monocytic (THP1) (but not erythroid- HEL) lineages are well adapted to VEGF and lactate rich environment. Their metabolic adaptation relies on high rates of glycolysis to generate intermediates for PPP to support cell proliferation, and on the consumption of glycolysis-generated lactate to supply biomass and energy production. VEGF orchestrates this metabolic network by regulating MCT1 expression. Bromopyruvic acid (BPA) was proven to be an effective cytotoxic in AML, possibly transported by MCT1.Our study reinforces that targeting metabolism can be a good strategy to fight cancer. MCT1 expression at the time of diagnosis can assist on the identification of AML patients that will benefit from BPA therapy. Additionally, MCT1 can be used in targeted delivery of conventional cytotoxic drugs.

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…A genomewide genetic screen identified MCT1 to be the main determinant of 3-bromopyruvate sensitivity in human cancer cell lines and tumor xenografts. 88 A recent study from Lopes-Coelho et al 89 confirms that MCT1 expression mediates 3-bromopyruvate transport in vitro using AML cell lines and suggests MCT1 expression as a predictive biomarker for response to 3-bromopyruvate treatment.…”

Revisiting the Crabtree/Warburg effect in a dynamic perspective: a fitness advantage against sugar-induced cell death

“…In such latter process, the occurrence of monocarboxylate transporters (MCTs) in the inner mitochondrial membrane, and a specific isoform of Ldh ensures the direct conversion of lactate into the mitochondrial pool of pyruvate [ 32 , 33 ]. Differently from yeast, some cancer cells, producing lactate in presence of high glucose concentration, are concomitantly able to respire it [ 29 , 30 ], thus showing a metabolic plasticity crucial for their adaptive success.…”

Highly Glycolytic Immortalized Human Dermal Microvascular Endothelial Cells are Able to Grow in Glucose-Starved Conditions

“…Additionally, 10 mM lactate failed to induce MCT1 protein expression (Figure 8e). HL-60 was used as positive control for MCT1 Western blot (Figure 8d,e) [27].…”