Abstract

Background

The liver is the central organ for cholesterol homoeostasis, and its dysfunction might cause liver pathological alterations including hepatocellular carcinomas (HCCs). 3β-hydroxysteroid-Δ24 reductase (DHCR24), a crucial enzyme of cholesterol biosynthetic pathway, is involved in lipid rafts formation. Genkwadaphnin (GD) is a daphnane diterpene isolated from the flower buds of Daphne genkwa Siebold et Zuccarini (Thymelaeaceae).

Methods

We evaluated in vitro and in vivo effect of GD using HCC cells and BALB/c nude mice. Microarray assays were used to identify the differential genes by GD. DHCR24 expression and activity, cholesterol level, lipid rafts structure and the role of DHCR24 in human HCC specimens were tested by various molecular biology techniques.

Results

High expression of DHCR24 in human HCC specimens was correlated with poor clinical outcome. Interfering DHCR24 altered growth and migration of HCC cells. GD inhibited growth and metastasis of HCC cells both in vivo and in vitro. GD suppressed DHCR24 expression and activity, as well as DHCR24-mediated cholesterol biosynthesis and lipid rafts formation, then further inhibited HCC cell invasion and migration.

Conclusions

Our data suggest that DHCR24-mediated cholesterol metabolism might be an effective therapeutic strategy in HCC, and natural product GD might be a promising agent for HCC therapy.

Details

Title
Genkwadaphnin inhibits growth and invasion in hepatocellular carcinoma by blocking DHCR24-mediated cholesterol biosynthesis and lipid rafts formation
Author
Wu, Jie 1 ; Guo, Ling 2 ; Qiu Xiaoran 2 ; Ren, Yong 3 ; Li, Feifei 1 ; Cui, Wei 2 ; Song Shaojiang 1   VIAFID ORCID Logo 

1  Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Shenyang, People’s Republic of China (GRID:grid.412561.5) (ISNI:0000 0000 8645 4345); Shenyang Pharmaceutical University, School of Traditional Chinese Materia Medica, Shenyang, People’s Republic of China (GRID:grid.412561.5) (ISNI:0000 0000 8645 4345) 
2  Shenyang Pharmaceutical University, School of Life Science and Biopharmaceutics, Shenyang, People’s Republic of China (GRID:grid.412561.5) (ISNI:0000 0000 8645 4345) 
3  Central Theater Command General Hospital PLA, Department of Pathology, Wuhan, People’s Republic of China (GRID:grid.412561.5) 
Pages
1673-1685
Publication year
2020
Publication date
Nov 2020
Publisher
Nature Publishing Group
ISSN
00070920
e-ISSN
15321827
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41416-020-01085-z
ProQuest document ID
2473249512
Copyright
© The Author(s), under exclusive licence to Cancer Research UK 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.