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.

• Authors: Po Hu, Hui Li, Xiaoxuan Yu, Xiao Liu, Xiangyuan Wang, Yingjie Qing, Zhanyu Wang, Hongzheng Wang, Mengyuan Zhu, Jingyan Xu, Renxiang Tan, Qinglong Guo, Hui Hui
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 145 Pg. 237-249 (12 2019) ISSN: 1873-4596 [Electronic] United States
• PMID: 31560953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl)butoxy)4H-chromen-4-one
• Bcl-2-Like Protein 11
• FOXO3 protein, human
• Flavonoids
• Forkhead Box Protein O3
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Bcl-2-Like Protein 11 (genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Flavonoids (pharmacology)
• Forkhead Box Protein O3 (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lysosomes (chemistry)
• Mice
• Phosphatidylinositol 3-Kinases (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, pathology)
• Proteolysis (drug effects)
• Proto-Oncogene Proteins c-akt (genetics)
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, pathology)
• Xenograft Model Antitumor Assays