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HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt
Author(s) -
Liu Hongwei,
Chen Qian,
Lu Di,
Pang Xu,
Yin Shuangshuang,
Wang Kailong,
Wang Rui,
Yang Shenshen,
Zhang Yi,
Qiu Yuling,
Wang Tao,
Yu Haiyang
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000254r
Subject(s) - protein kinase b , alkaloid , carcinogenesis , chemistry , cancer research , pharmacology , traditional medicine , medicine , signal transduction , biochemistry , stereochemistry , gene
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, (13a R ,14 R )‐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.