GL-V9 exerts anti-T cell malignancies effects via promoting lysosome-dependent AKT1 degradation and activating AKT1/FOXO3A/BIM axis

Abstract

T-cell malignancies are characterized by the excessive proliferation of hematopoietic precursor cells of T-cell lineage lymphocytes in the bone marrow. Previous studies suggest that T-cell malignancies are usually accompanied by highly activated PI3K/AKT signaling which confers the ability of cancer cells to proliferate and survive. Here, we found that GL-V9, a newly synthesized flavonoid compound, had a potent to inhibit the activation of AKT1 and induce the cell apoptosis in T-cell malignancies including cell lines and primary lymphoblastic leukemia. Results showed that GL-V9-induced degradation of AKT1 blocked PI3K/AKT1 signaling and the degradation of AKT1 could be reversed by NH₄Cl, an inhibitor of lysosomal function. Inhibiting AKT1 promoted dephosphorylation of FOXO3A and its nuclear translocation. We further demonstrated that GL-V9-induced apoptosis effects were dependent on the binding of FOXO3A to the BIM promoter, resulting in the production of BH3-only protein BIM. Moreover, GL-V9 showed a more persistent and stronger apoptosis induction effects than pharmacologic PI3K inhibitor. The in vivo studies also verified that GL-V9 possessed the anti-tumor effects by reducing the leukemic burden in T-ALL-bearing BALB/c nude mice. In conclusion, our study provides a new insight into the mechanism of GL-V9-induced apoptosis, suggesting the potency of GL-V9 to be a promising agent against T-cell malignancies.

Keywords: BIM; FOXO3A; GL-V9; PI3K/AKT1 signaling; T-cell malignancies; apoptosis.