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Glucose Metabolism in Acute Myeloid Leukemia Cell Line Is Regulated via Combinational PI3K/AKT/mTOR Pathway

Abbas Ranjbar1,2, Mohsen Soltanshahi1,2, Saeid Taghiloo1

  • 1Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Iranian Journal of Pharmaceutical Research : IJPR
|March 4, 2024
PubMed
Abstract

Insights

Combination therapy targeting the PI3K/AKT/mTOR pathway in acute myeloid leukemia (AML) cells reduces key metabolic gene expression. This approach may offer a novel strategy against AML metabolic reprogramming and immune evasion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Metabolic reprogramming is crucial for acute myeloid leukemia (AML) cell survival within the tumor microenvironment.
  • Investigating signaling pathway inhibitors' effects on metabolic gene expression in AML is vital.

Purpose of the Study:

  • To examine how selective inhibitors of phosphatidylinositol-3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) affect metabolic gene expression in AML cells.
  • To determine the impact of combined PI3K/AKT/mTOR pathway inhibition on AML cell metabolism.

Main Methods:

  • HL-60 cells were treated with Idelalisib (PI3K inhibitor), MK-2206 (AKT inhibitor), and Everolimus (mTOR inhibitor) individually and in combination.
  • Real-time PCR was used to quantify the relative expression of genes involved in glucose metabolism, the pyruvate dehydrogenase complex, and the TCA cycle.

Main Results:

  • Combined treatment with Idelalisib, MK-2206, and Everolimus significantly decreased the expression of key metabolic genes.
  • Specifically, glucose transporter 1, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase E1, citrate synthase, isocitrate dehydrogenase 2, and hypoxia inducible factor 1 subunit alpha expression were reduced.

Conclusions:

  • Combined PI3K/AKT/mTOR pathway inhibition effectively regulates genes in glycolysis, the pyruvate dehydrogenase complex (PDH), and the tricarboxylic acid (TCA) cycle.
  • This combinational therapy interferes with metabolic reprogramming and immune evasion in AML cells.
  • Targeting these metabolic pathways offers a promising therapeutic strategy for AML.
Keywords:
Acute Myeloid LeukemiaCitric Acid CycleGlycolysisPI3K/AKT/mTORSignaling Pathways

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