HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt
HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt
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HTBPI 是一种活性菲并吲哚里西啶生物碱，通过靶向 Akt 抑制肝脏肿瘤发生
DOI：
10.1096/fj.202000254r
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发表时间：
2020-07-24
期刊：
影响因子：
4.8
通讯作者：
Yu, Haiyang
中科院分区：
文献类型：
--
作者：
Liu, Hongwei;Chen, Qian;Yu, Haiyang
Akt是参与多种肿瘤信号通路的重要蛋白，是肝细胞癌（HCC）存活的重要调节因子，为相关药物的开发提供治疗选择。我们发现了一种活性的phenanthroindolizidine生物碱，（13aR,14R）‐9,11,12,13,13a,14‐hexahydro‐3,6,7‐trimethoxydibenzo[f,h]pyrrolo[1,2‐b]isoquinolin‐14‐ol (HTBPI)，是一种很有前景的Akt抑制剂，通过刺激细胞凋亡和自噬能力，在体内和体外有效抑制HCC细胞增殖。HTBPI联合经典的自噬溶酶体抑制剂（巴菲霉素A1）可增强对HCC细胞系的凋亡刺激作用。此外，我们通过CETSA和DARTS实验证实HTBPI靶向Akt，占据Akt的激酶结合结构域（Thr 308）使其失活。相反，异位Akt诱导的过表达显著消除了HTBPI对细胞活力和增殖的抑制作用。此外，高表达的p - Akt （Thr 308）与肝癌患者的肝肿瘤形成和生存率低有关。总之，HTBPI通过与p - Akt相互作用调节细胞凋亡和自噬机制，从而阻碍HCC进展（Thr 308）。这可能为靶向Akt治疗HCC患者提供潜在的分子候选物。
Akt, a crucial protein involved in a variety of signaling pathways in cancer, acts as an important regulator of survival in hepatocellular carcinoma (HCC), and provides curative option for the related drugs development. We have found an active phenanthroindolizidine alkaloid, (13aR,14R)‐9,11,12,13,13a,14‐hexahydro‐3,6,7‐trimethoxydibenzo[f,h]pyrrolo[1,2‐b]isoquinolin‐14‐ol (HTBPI), is a promising Akt inhibitor effective in the suppression of HCC cells proliferation through stimulating apoptotic and autophagic capability in vivo and in vitro. Treatment of HTBPI combined with a classical autophagy‐lysosomal inhibitor (bafilomycin A1), could enhance stimulation effects of apoptosis on HCC cell lines. In addition, we confirmed HTBPI targeting Akt, occupied the kinase binding domain (Thr 308) of Akt to inactivate its function by CETSA and DARTS assay. In contrast, ectopic Akt‐induced overexpression significantly abrogated inhibitory effects of HTBPI on cell viability and proliferation. Furthermore, high p‐Akt (Thr 308) expression is collated with liver tumor formation and poor survival in HCC patients. In conclusions, HTBPI impeded HCC progress through regulation of apoptosis and autophagy machinery via interaction with p‐Akt (Thr 308). This may provide potential molecular candidate by targeting Akt for the therapy of HCC patients.