PTEN/AKT signaling mediates chemoresistance in refractory acute myeloid leukemia through enhanced glycolysis

Primary refractory acute myeloid leukemia (AML) and early recurrence of leukemic cells are among the most difficult hurdles to overcome in the treatment of AML. Moreover, uncertainties surrounding the molecular mechanism underlying refractory AML pose a challenge when it comes to developing novel therapeutic drugs. However, accumulating evidence suggests a contribution of phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling to the development of refractory AML. To assess PTEN/AKT signaling in AML, two types of AML cell lines were evaluated, namely control HL60 cells and KG1 alpha cells, a refractory AML cell line that is resistant to idarubicin and cytarabine (AraC) treatment. Changes in the expression level of glycolysis- and mitochondrial oxidative phosphorylation-related genes and proteins were evaluated by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The mitochondrial oxygen consumption and extracellular acidification rates were measured using an XF24 analyzer. CCK8 assay and Annexin V/PI staining were used to analyze cell viability and cellular apoptosis, respectively. The PTEN protein was found to be depleted, whereas AKT phosphorylation levels were elevated in KG1 alpha cells compared with HL60 cells. These changes were associated with increased expression of glucose transporter 1 and hexokinase 2, and increased lactate production. AKT inhibition decreased the proliferation of KG1 alpha cells and decreased extracellular acidification without affecting HL60 cells. Notably, AKT inhibition increased the susceptibility of KG1 alpha cells to chemotherapy with idarubicin and AraC. Taken together, the findings of the present study indicate that activation of AKT by PTEN deficiency sustains the refractory AML status through enhancement of glycolysis and mitochondrial respiration, effects that may be rescued by inhibiting AKT activity.