한빛사 논문
Min Jeong Ryu1,2, Jeongsu Han1,3, Soo Jeong Kim1,3, Min Joung Lee1-4, Xianshu Ju1,3,4, Yu Lim Lee1,3,4, Jeong Hwan Son4, Jianchen Cui1,3,4, Yunseon Jang1,3,4, Woosuk Chung5,6, Ik‑Chan Song7, Gi Ryang Kweon1,2,4,*, Jun Young Heo1,3-5,*
1Department of Biochemistry, College of Medicine; 2Research Institute for Medical Science; 3Infection Control Convergence Research Center; 4Department of Medical Science; 5Brain Research Institute, Chungnam National University School of Medicine; Departments of 6Anesthesiology and Pain Medicine, and 7Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
*Correspondence to: Dr Jun Young Heo or Professor Gi Ryang Kweon
Abstract
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 KG1α 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 KG1α 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 KG1α cells and decreased extracellular acidification without affecting HL60 cells. Notably, AKT inhibition increased the susceptibility of KG1α 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.
Key words: refractory acute myeloid leukemia, chemoresistance, phosphatase and tensin homolog, protein kinase B, glycolysis
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