Role of glucose metabolism in the differential antileukemic effect of melatonin on wildtype and FLT3ITD mutant cells.
Oncol Rep
; 44(1): 293-302, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32319665
ABSTRACT
The FMSlike tyrosine kinase 3 internal tandem duplication (FLT3ITD) mutation represents the most frequent genetic alteration in acute myeloid leukemia (AML) and is associated with poor prognosis. The mutation promotes cancer cell survival and proliferation, and shifts their glucose metabolism towards aerobic glycolysis, a frequent alteration in cancer. In the present study, the impact of melatonin on the viability of AML cell lines with (MV411 and MOLM13) or without the FLT3ITD mutation (OCIAML3 and U937) was evaluated. Melatonin induces cell death in AML cells carrying the FLT3ITD mutation, but only inhibits the proliferation of AML cells without this mutation. Consistently, melatonin decreases tumor growth and increases animal survival in a xenograft model of FLT3ITD AML. Toxicity is related to a decrease in glucose uptake, lactate dehydrogenase activity, lactate production and hypoxiainducible factor1α activation. Melatonin also regulates the expression of glucose metabolismrelated genes, impairing the balance between anaplerosis and cataplerosis, through the upregulation of the expression of phosphoenolpyruvate carboxykinase 2 (PCK2). Collectively, the present findings highlight the regulation of glucose metabolism, currently considered a possible therapeutic target in cancer, as a key event in melatonininduced cytotoxicity, suggesting its potential as a therapeutic tool for the treatment of patients with AML, particularly those carrying the FLT3ITD mutation that results in low basal expression levels of PCK2.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
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Tirosina Quinase 3 Semelhante a fms
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Glucose
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Melatonina
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article