Targeting Lactate Metabolism by Inhibiting MCT1 or MCT4 Impairs Leukemic Cell Proliferation, Induces Two Different Related Death-Pathways and Increases Chemotherapeutic Sensitivity of Acute Myeloid Leukemia Cells.

Ernestina Saulle,Luca Pasquini,Germana Castelli,Maria Teresa Voso,Maria Elena Pisanu,Catherine Labbaye,Maria Teresa Quaranta,Ugo Testa,Isabella Spinello,Egidio Iorio,Mattea Chirico,Tiziana Ottone,Elvira Pelosi

doi:10.3389/fonc.2020.621458

Abstract

Metabolism in acute myeloid leukemia (AML) cells is dependent primarily on oxidative phosphorylation. However, in order to sustain their high proliferation rate and metabolic demand, leukemic blasts use a number of metabolic strategies, including glycolytic metabolism. Understanding whether monocarboxylate transporters MCT1 and MCT4, which remove the excess of lactate produced by cancer cells, represent new hematological targets, and whether their respective inhibitors, AR-C155858 and syrosingopine, can be useful in leukemia therapy, may reveal a novel treatment strategy for patients with AML. We analyzed MCT1 and MCT4 expression and function in hematopoietic progenitor cells from healthy cord blood, in several leukemic cell lines and in primary leukemic blasts from patients with AML, and investigated the effects of AR-C155858 and syrosingopine, used alone or in combination with arabinosylcytosine, on leukemic cell proliferation. We found an inverse correlation between MCT1 and MCT4 expression levels in leukemic cells, and showed that MCT4 overexpression is associated with poor prognosis in AML patients. We also found that AR-C155858 and syrosingopine inhibit leukemic cell proliferation by activating two different cell-death related pathways, i.e., necrosis for AR-C155858 treatment and autophagy for syrosingopine, and showed that AR-C155858 and syrosingopine exert an anti-proliferative effect, additive to chemotherapy, by enhancing leukemic cells sensitivity to chemotherapeutic agents. Altogether, our study shows that inhibition of MCT1 or MCT4 impairs leukemic cell proliferation, suggesting that targeting lactate metabolism may be a new therapeutic strategy for AML, and points to MCT4 as a potential therapeutic target in AML patients and to syrosingopine as a new anti-proliferative drug and inducer of autophagy to be used in combination with conventional chemotherapeutic agents in AML treatment.

Highlights

Cancerous tissue and cells run high rate of glycolysis and rely on pyruvate reduction to lactate for energy production to support their proliferation and anabolic growth under oxidative stress and hypoxia, or under aerobic conditions, a phenomenon referred to as “the Warburg effect” [1,2,3]
We explored the use of their inhibitors, ARC155858 (AR-C), a specific inhibitor of MCT1 and MCT2, and syrosingopine (SYRO), previously described as a dual MCT1 and MCT4 inhibitor but with a major affinity for MCT4, to reduce glycolysis and evaluate their effects on leukemic cell proliferation in vitro, in combination or not, with the more conventional chemotherapeutic agent used in myeloid leukemia, arabinosylcytosine (Ara-C) [8, 27, 28]
Our data show that MCT1 and MCT4 play a key role in leukemic cell proliferation and suggest that lactate metabolism is a potential target for acute myeloid leukemia (AML) therapy, through MCT4 inhibition by SYRO, an inducer of autophagy with a major affinity for MCT4 whose overexpression is correlated with poor prognosis in AML, to be used in combination with conventional chemotherapeutic agents as a novel treatment strategy in AML

Summary

INTRODUCTION

Cancerous tissue and cells run high rate of glycolysis and rely on pyruvate reduction to lactate for energy production to support their proliferation and anabolic growth under oxidative stress and hypoxia, or under aerobic conditions, a phenomenon referred to as “the Warburg effect” [1,2,3]. MCT1 mediates the bidirectional high-affinity transport of monocarboxylates, including lactate, pyruvate, acetate, and D, L-b-hydroxybutyrate while MCT4 mediates the export of lactate in highly glycolytic cells [6, 10] Both MCT1 and MCT4 require the association with the multifunctional transmembrane glycoprotein CD147, called basigin or EMMPRIN (Extracellular Matrix MetalloPRoteinase Inducer), for their correct functionality and translocation to the plasma membrane where they act [11,12,13,14]. Our data show that MCT1 and MCT4 play a key role in leukemic cell proliferation and suggest that lactate metabolism is a potential target for AML therapy, through MCT4 inhibition by SYRO, an inducer of autophagy with a major affinity for MCT4 whose overexpression is correlated with poor prognosis in AML, to be used in combination with conventional chemotherapeutic agents as a novel treatment strategy in AML

MATERIALS AND METHODS

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DISCUSSION

ETHICS STATEMENT