Role of glucose metabolism in the differential antileukemic effect of melatonin on wild‑type and FLT3‑ITD mutant cells

Puente‑Moncada,Noelia; Turos‑Cabal,Maria; Sánchez‑Sánchez,Ana  M.; Antolín,Isaac; Herrera,Federico; Rodriguez‑Blanco,Jezabel; Duarte‑Olivenza,Cristina; Rodriguez,Carmen; Martín,Vanesa

doi:10.3892/or.2020.7584

Role of glucose metabolism in the differential antileukemic effect of melatonin on wild‑type and FLT3‑ITD mutant cells

Authors:
- Noelia Puente‑Moncada
- Maria Turos‑Cabal
- Ana M. Sánchez‑Sánchez
- Isaac Antolín
- Federico Herrera
- Jezabel Rodriguez‑Blanco
- Cristina Duarte‑Olivenza
- Carmen Rodriguez
- Vanesa Martín
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Affiliations: Departamento de Morfología y Biología Celular, Facultad de Medicina, University of Oviedo, 33006 Oviedo, Spain, Facultade de Ciencias, Biosystems and Integrative Sciences Institute, Universidade de Lisboa, 1749‑016 Lisbon, Portugal, Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
Published online on: April 15, 2020 https://doi.org/10.3892/or.2020.7584
Pages: 293-302

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Abstract

The FMS‑like tyrosine kinase 3 internal tandem duplication (FLT3‑ITD) 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 (MV‑4‑11 and MOLM‑13) or without the FLT3‑ITD mutation (OCI‑AML3 and U‑937) was evaluated. Melatonin induces cell death in AML cells carrying the FLT3‑ITD 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 FLT3‑ITD AML. Toxicity is related to a decrease in glucose uptake, lactate dehydrogenase activity, lactate production and hypoxia‑inducible factor‑1α activation. Melatonin also regulates the expression of glucose metabolism‑related 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 melatonin‑induced cytotoxicity, suggesting its potential as a therapeutic tool for the treatment of patients with AML, particularly those carrying the FLT3‑ITD mutation that results in low basal expression levels of PCK2.

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