Inhibition of PI3K/AKT/mTOR signaling enhances autophagy in HL-60 acute myeloid leukemia cells: An integrative bioinformatic and in vitro study

Abstract

Background: Acute myeloid leukemia (AML) involves uncontrolled proliferation of myeloid progenitor cells and carries a poor prognosis. The PI3K/AKT/mTOR pathway plays a key role in AML pathogenesis by regulating cancer cell proliferation and survival. This study investigates the effects of inhibiting the PI3K/AKT/mTOR pathway on autophagy in AML cell lines, aiming to support targeted therapy development that modulates autophagy. Methods: Gene expression and prognostic significance of PI3K/AKT/mTOR and autophagy-related genes in AML were evaluated using Enricher, GEPIA2, and Human Protein Atlas databases. HL-60 cells were treated with Idelalisib, MK-2206, and Everolimus, selective PI3K, AKT, and mTOR inhibitors, either individually or in combination. Autophagy gene expression (Beclin-1, LC3-II, Atg5, ATG7) was assessed by Real-time PCR. Result: Bioinformatic analysis revealed that autophagy genes are associated with PI3K/AKT/mTOR pathway in AML. We observed that HL-60 AML cell lines treated with PI3K/AKT/mTOR inhibitors exhibited significant enhancement in the expression of key autophagy-related genes, including Beclin-1, LC3-II, ATG5, and ATG7, particularly with combination treatment. Conclusion: PI3K/AKT/mTOR inhibitors significantly induce autophagy-related gene expression in AML cells. These findings support combining such inhibitors with autophagy modulators as a potential strategy to improve AML treatment outcomes.

Keywords

• Acute myeloid leukemia
• PI3K/AKT/mTOR
• Autophagy
• Idelalisib
• MK 2206
• Everolimus