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Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells

Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mecha...

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Autores principales: Oliveira, Thaís, Lemos, Douglas, Jean, Louise, Kawashima, Jéssica M., de Azevedo, Vitória R., Salustiano, Eduardo J., Rumjanek, Vivian M., Monteiro, Robson Q.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204307/
https://www.ncbi.nlm.nih.gov/pubmed/35719932
http://dx.doi.org/10.3389/fonc.2022.852985
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author Oliveira, Thaís
Lemos, Douglas
Jean, Louise
Kawashima, Jéssica M.
de Azevedo, Vitória R.
Salustiano, Eduardo J.
Rumjanek, Vivian M.
Monteiro, Robson Q.
author_facet Oliveira, Thaís
Lemos, Douglas
Jean, Louise
Kawashima, Jéssica M.
de Azevedo, Vitória R.
Salustiano, Eduardo J.
Rumjanek, Vivian M.
Monteiro, Robson Q.
author_sort Oliveira, Thaís
collection PubMed
description Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mechanisms relies on the high expression of efflux transporters, such as the ABC proteins, whose activity depends on the hydrolysis of ATP to reduce intracellular drug accumulation. In the present work, we employed a well-known erythroleukemia cell line, K562, and a multidrug resistant derivative cell, FEPS, to evaluate how hexokinase II, a key regulator for the rate-limiting step glycolysis, contributes to the establishment of the multidrug resistance phenotype. We found that multidrug resistant cells primarily resort to glycolysis to generate ATP. Clotrimazole reduced the expression of mitochondrial hexokinase II, which destabilized bioenergetic parameters such as reactive oxygen species production, ATP, and glutathione levels on multidrug resistant cells. This impaired the activity of ABCC1, leading to increased drug accumulation and cell death. In summary, we propose that decoupling of hexokinase II from the mitochondria emerges as a promising strategy to generate collateral sensitivity and aid in the management of chronic myeloid leukemia in chemotherapy-refractory patients.
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spelling pubmed-92043072022-06-18 Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells Oliveira, Thaís Lemos, Douglas Jean, Louise Kawashima, Jéssica M. de Azevedo, Vitória R. Salustiano, Eduardo J. Rumjanek, Vivian M. Monteiro, Robson Q. Front Oncol Oncology Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mechanisms relies on the high expression of efflux transporters, such as the ABC proteins, whose activity depends on the hydrolysis of ATP to reduce intracellular drug accumulation. In the present work, we employed a well-known erythroleukemia cell line, K562, and a multidrug resistant derivative cell, FEPS, to evaluate how hexokinase II, a key regulator for the rate-limiting step glycolysis, contributes to the establishment of the multidrug resistance phenotype. We found that multidrug resistant cells primarily resort to glycolysis to generate ATP. Clotrimazole reduced the expression of mitochondrial hexokinase II, which destabilized bioenergetic parameters such as reactive oxygen species production, ATP, and glutathione levels on multidrug resistant cells. This impaired the activity of ABCC1, leading to increased drug accumulation and cell death. In summary, we propose that decoupling of hexokinase II from the mitochondria emerges as a promising strategy to generate collateral sensitivity and aid in the management of chronic myeloid leukemia in chemotherapy-refractory patients. Frontiers Media S.A. 2022-05-26 /pmc/articles/PMC9204307/ /pubmed/35719932 http://dx.doi.org/10.3389/fonc.2022.852985 Text en Copyright © 2022 Oliveira, Lemos, Jean, Kawashima, de Azevedo, Salustiano, Rumjanek and Monteiro https://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
Oliveira, Thaís
Lemos, Douglas
Jean, Louise
Kawashima, Jéssica M.
de Azevedo, Vitória R.
Salustiano, Eduardo J.
Rumjanek, Vivian M.
Monteiro, Robson Q.
Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells
title Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells
title_full Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells
title_fullStr Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells
title_full_unstemmed Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells
title_short Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells
title_sort detachment of hexokinase ii from mitochondria promotes collateral sensitivity in multidrug resistant chronic myeloid leukemia cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204307/
https://www.ncbi.nlm.nih.gov/pubmed/35719932
http://dx.doi.org/10.3389/fonc.2022.852985
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