GL-V9 exerts anti-T cell malignancies effects via promoting lysosome-dependent AKT1 degradation and activating AKT1/FOXO3A/BIM axis
GL-V9 exerts anti-T cell malignancies effects via promoting lysosome-dependent AKT1 degradation and activating AKT1/FOXO3A/BIM axis
复制标题
GL-V9通过促进溶酶体依赖性AKT1降解和激活AKT1/FOXO3A/BIM轴发挥抗T细胞恶性肿瘤作用
DOI：
10.1016/j.freeradbiomed.2019.09.028
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发表时间：
2019-12-01
影响因子：
7.4
通讯作者：
Hui, Hui
中科院分区：
文献类型：
--
作者：
Hu, Po;Li, Hui;Hui, Hui
T细胞恶性肿瘤的特征在于骨髓中T细胞谱系淋巴细胞的造血前体细胞的过度增殖。先前的研究表明，T细胞恶性肿瘤通常伴随着高度活化的PI 3 K/AKT信号传导，其赋予癌细胞增殖和存活的能力。本研究发现，GL-V9是一种新合成的黄酮类化合物，在T细胞恶性肿瘤包括细胞系和原发性淋巴细胞白血病中具有抑制AKT 1活化和诱导细胞凋亡的作用。结果表明，GL-V9诱导的AKT 1降解阻断了PI 3 K/AKT 1信号通路，并且AKT 1的降解可以被溶酶体功能抑制剂NH 4Cl逆转。抑制AKT 1促进FOXO 3A的去磷酸化及其核转位。我们进一步证明GL-V9诱导的细胞凋亡效应依赖于FOXO 3A与BIM启动子的结合，导致仅BH 3蛋白BIM的产生。此外，GL-V9显示出比药理学PI 3 K抑制剂更持久和更强的凋亡诱导作用。体内实验也证实GL-V9具有降低荷T-ALL BALB/c裸鼠白血病负荷的抗肿瘤作用。总之，我们的研究为GL-V9诱导细胞凋亡的机制提供了新的见解，表明GL-V9是一种有前途的抗T细胞恶性肿瘤药物。
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 antitumor 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.