Abstract
BackgroundThe 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).MethodsWe 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.ResultsHigh 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.ConclusionsOur 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.
Highlights
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
We found that GD was an effective anti-HCC agent by suppressing DHCR24mediated cholesterol biosynthesis and lipid rafts formation, and by inhibiting HCC cells growth and metastasis
GD reduces the viability of hepatocellular carcinoma cells Our previous studies showed that several daphnane-type diterpenes isolated from flower buds of Daphne genkwa had significant cytotoxic activities.[7,11]
Summary
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. 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, further inhibited HCC cell invasion and migration. There is an urgent need for better understanding of the molecular basis of HCC in order to develop effective treatment strategies to improve survival of patients with unresectable hepatic malignancies
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