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Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells

Since many oncogenes, including BCR-ABL, may promote the acquisition and maintenance of the glycolytic phenotype, we tested whether treatment of BCR-ABL-driven human leukemia cells with imatinib, a selective BCR-ABL inhibitor, can modulate the expression of key glycolytic enzymes and mitochondrial c...

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Autores principales: De Rosa, Viviana, Monti, Marcello, Terlizzi, Cristina, Fonti, Rosa, Del Vecchio, Silvana, Iommelli, Francesca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651622/
https://www.ncbi.nlm.nih.gov/pubmed/31252559
http://dx.doi.org/10.3390/ijms20133134
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author De Rosa, Viviana
Monti, Marcello
Terlizzi, Cristina
Fonti, Rosa
Del Vecchio, Silvana
Iommelli, Francesca
author_facet De Rosa, Viviana
Monti, Marcello
Terlizzi, Cristina
Fonti, Rosa
Del Vecchio, Silvana
Iommelli, Francesca
author_sort De Rosa, Viviana
collection PubMed
description Since many oncogenes, including BCR-ABL, may promote the acquisition and maintenance of the glycolytic phenotype, we tested whether treatment of BCR-ABL-driven human leukemia cells with imatinib, a selective BCR-ABL inhibitor, can modulate the expression of key glycolytic enzymes and mitochondrial complex subunits thus causing alterations of glucose metabolism. BCR-ABL-driven K562 and KCL-22 cells were incubated with increasing concentrations of imatinib to preliminarily test drug sensitivity. Then untreated and treated cells were analyzed for levels of BCR-ABL signaling mediators and key proteins of glycolytic cascade and oxidative phosphorylation. Effective inhibition of BCR-ABL caused a concomitant reduction of p-ERK1/2, p-AKT, phosphorylated form of STAT3 (at Tyr705 and Ser727), c-Myc and cyclin D1 along with an increase of cleaved PARP and caspase 3 at 48 h after treatment. Furthermore, a strong reduction of the hexokinase II (HKII), phosphorylated form of PKM2 (at Tyr105 and Ser37) and lactate dehydrogenase A (LDH-A) was observed in response to imatinib along with a strong upregulation of mitochondrial complexes (OXPHOS). According to these findings, a significant reduction of glucose consumption and lactate secretion along with an increase of intracellular ATP levels was observed in response to imatinib. Our findings indicate that imatinib treatment of BCR-ABL-driven human leukemia cells reactivates mitochondrial oxidative phosphorylation thus allowing potential co-targeting of BCR-ABL and OXPHOS.
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spelling pubmed-66516222019-08-08 Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells De Rosa, Viviana Monti, Marcello Terlizzi, Cristina Fonti, Rosa Del Vecchio, Silvana Iommelli, Francesca Int J Mol Sci Communication Since many oncogenes, including BCR-ABL, may promote the acquisition and maintenance of the glycolytic phenotype, we tested whether treatment of BCR-ABL-driven human leukemia cells with imatinib, a selective BCR-ABL inhibitor, can modulate the expression of key glycolytic enzymes and mitochondrial complex subunits thus causing alterations of glucose metabolism. BCR-ABL-driven K562 and KCL-22 cells were incubated with increasing concentrations of imatinib to preliminarily test drug sensitivity. Then untreated and treated cells were analyzed for levels of BCR-ABL signaling mediators and key proteins of glycolytic cascade and oxidative phosphorylation. Effective inhibition of BCR-ABL caused a concomitant reduction of p-ERK1/2, p-AKT, phosphorylated form of STAT3 (at Tyr705 and Ser727), c-Myc and cyclin D1 along with an increase of cleaved PARP and caspase 3 at 48 h after treatment. Furthermore, a strong reduction of the hexokinase II (HKII), phosphorylated form of PKM2 (at Tyr105 and Ser37) and lactate dehydrogenase A (LDH-A) was observed in response to imatinib along with a strong upregulation of mitochondrial complexes (OXPHOS). According to these findings, a significant reduction of glucose consumption and lactate secretion along with an increase of intracellular ATP levels was observed in response to imatinib. Our findings indicate that imatinib treatment of BCR-ABL-driven human leukemia cells reactivates mitochondrial oxidative phosphorylation thus allowing potential co-targeting of BCR-ABL and OXPHOS. MDPI 2019-06-27 /pmc/articles/PMC6651622/ /pubmed/31252559 http://dx.doi.org/10.3390/ijms20133134 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
De Rosa, Viviana
Monti, Marcello
Terlizzi, Cristina
Fonti, Rosa
Del Vecchio, Silvana
Iommelli, Francesca
Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
title Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
title_full Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
title_fullStr Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
title_full_unstemmed Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
title_short Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
title_sort coordinate modulation of glycolytic enzymes and oxphos by imatinib in bcr-abl driven chronic myelogenous leukemia cells
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651622/
https://www.ncbi.nlm.nih.gov/pubmed/31252559
http://dx.doi.org/10.3390/ijms20133134
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