Genkwadaphnin inhibits growth and invasion in hepatocellular carcinoma by blocking DHCR24-mediated cholesterol biosynthesis and lipid rafts formation.

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.

• Authors: Jie Wu, Ling Guo, Xiaoran Qiu, Yong Ren, Feifei Li, Wei Cui, Shaojiang Song
• Journal: British journal of cancer (Br J Cancer) Vol. 123 Issue 11 Pg. 1673-1685 (11 2020) ISSN: 1532-1827 [Electronic] England
• PMID: 32958824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Diterpenes
• Nerve Tissue Proteins
• Plant Extracts
• genkwadaphnin
• Cholesterol
• Oxidoreductases Acting on CH-CH Group Donors
• DHCR24 protein, human

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Carcinoma, Hepatocellular (metabolism, pathology)
• Cell Proliferation (drug effects)
• Cholesterol (biosynthesis)
• Diterpenes (pharmacology)
• Humans
• Liver Neoplasms (metabolism, pathology)
• Membrane Microdomains (drug effects)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness (pathology)
• Nerve Tissue Proteins (metabolism)
• Oxidoreductases Acting on CH-CH Group Donors (metabolism)
• Plant Extracts (pharmacology)
• Xenograft Model Antitumor Assays