Cargando…

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

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 monocarb...

Descripción completa

Detalles Bibliográficos
Autores principales: Saulle, Ernestina, Spinello, Isabella, Quaranta, Maria Teresa, Pasquini, Luca, Pelosi, Elvira, Iorio, Egidio, Castelli, Germana, Chirico, Mattea, Pisanu, Maria Elena, Ottone, Tiziana, Voso, Maria Teresa, Testa, Ugo, Labbaye, Catherine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892602/
https://www.ncbi.nlm.nih.gov/pubmed/33614502
http://dx.doi.org/10.3389/fonc.2020.621458
_version_ 1783652882464112640
author Saulle, Ernestina
Spinello, Isabella
Quaranta, Maria Teresa
Pasquini, Luca
Pelosi, Elvira
Iorio, Egidio
Castelli, Germana
Chirico, Mattea
Pisanu, Maria Elena
Ottone, Tiziana
Voso, Maria Teresa
Testa, Ugo
Labbaye, Catherine
author_facet Saulle, Ernestina
Spinello, Isabella
Quaranta, Maria Teresa
Pasquini, Luca
Pelosi, Elvira
Iorio, Egidio
Castelli, Germana
Chirico, Mattea
Pisanu, Maria Elena
Ottone, Tiziana
Voso, Maria Teresa
Testa, Ugo
Labbaye, Catherine
author_sort Saulle, Ernestina
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7892602
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-78926022021-02-20 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 Saulle, Ernestina Spinello, Isabella Quaranta, Maria Teresa Pasquini, Luca Pelosi, Elvira Iorio, Egidio Castelli, Germana Chirico, Mattea Pisanu, Maria Elena Ottone, Tiziana Voso, Maria Teresa Testa, Ugo Labbaye, Catherine Front Oncol Oncology 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. Frontiers Media S.A. 2021-02-05 /pmc/articles/PMC7892602/ /pubmed/33614502 http://dx.doi.org/10.3389/fonc.2020.621458 Text en Copyright © 2021 Saulle, Spinello, Quaranta, Pasquini, Pelosi, Iorio, Castelli, Chirico, Pisanu, Ottone, Voso, Testa and Labbaye http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Saulle, Ernestina
Spinello, Isabella
Quaranta, Maria Teresa
Pasquini, Luca
Pelosi, Elvira
Iorio, Egidio
Castelli, Germana
Chirico, Mattea
Pisanu, Maria Elena
Ottone, Tiziana
Voso, Maria Teresa
Testa, Ugo
Labbaye, Catherine
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892602/
https://www.ncbi.nlm.nih.gov/pubmed/33614502
http://dx.doi.org/10.3389/fonc.2020.621458
work_keys_str_mv AT saulleernestina targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT spinelloisabella targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT quarantamariateresa targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT pasquiniluca targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT pelosielvira targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT iorioegidio targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT castelligermana targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT chiricomattea targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT pisanumariaelena targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT ottonetiziana targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT vosomariateresa targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT testaugo targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells
AT labbayecatherine targetinglactatemetabolismbyinhibitingmct1ormct4impairsleukemiccellproliferationinducestwodifferentrelateddeathpathwaysandincreaseschemotherapeuticsensitivityofacutemyeloidleukemiacells