Abstract
Actinidia chinensis Planch root extract (acRoots) is a traditional Chinese medicine with anti-tumor efficacy. To investigate the mechanisms responsible for this activity, we examined the effects of acRoots on cholesterol metabolism in hepatocellular carcinoma (HCC). mRNA chip analysis was used to identify the metabolic genes regulated by acRoots. The effects of acRoots on cholesterol synthesis and uptake were evaluated by measuring intracellular cholesterol levels and 3,3′-dioctadecylindocarbocyanine-labeled low-density lipoprotein (Dil-LDL) uptake. Expression of metabolic genes was analyzed using quantitative reverse transcription PCR, western blotting, and flow cytometry. acRoots reduced the viability of LM3 and HepG2 cells at 5 mg/mL and HL-7702 cells at 30 mg/mL. Gene expression profiling revealed that treatment with acRoots altered expression of genes involved in immune responses, inflammation, proliferation, cell cycle control, and metabolism. We also confirmed that acRoots enhances expression of PCSK9, which is important for cholesterol metabolism. This resulted in decreased LDL receptor expression, inhibition of LDL uptake by LM3 cells, decreased total intracellular cholesterol, and reduced proliferation. These effects were promoted by PCSK9 overexpression and rescued by PCSK9 knockdown. Our data demonstrate that acRoots is a novel anti-tumor agent that inhibits cholesterol metabolism though a PCSK9-mediated signaling pathway.
Highlights
Hepatocellular carcinoma (HCC) is a malignant tumor of the liver
To investigate the mechanisms responsible for this activity, we examined the effects of acRoots on cholesterol metabolism in hepatocellular carcinoma (HCC). mRNA chip analysis was used to identify the metabolic genes regulated by acRoots
We found that several members of the steroid and terpenoid backbone biosynthesis pathways were significantly up-regulated in LM3 cells (Figure 1G, Supplementary Figure 1C and 1D), suggesting that acRoots altered steroid metabolism in HCC cells
Summary
Hepatocellular carcinoma (HCC) is a malignant tumor of the liver. It is the third most common cause of cancer-related death worldwide [1, 2]. The 5-year survival rate for HCC patients is 15% (localized, 28%; regional, 7%; and distant, 3%), and 80-90% of patients present with advanced and unresectable tumors at the time of diagnosis due to widespread intraand extra-hepatic metastasis [4]. It is critical to elucidate the molecular mechanisms underlying HCC progression and develop novel treatment strategies. Several drugs have shown efficacy in HCC including the multikinase inhibitor Sorafenib (targets Raf, VEGFR, PDGFRβ, c-Kit, RET, and other kinases), which is approved for clinical use. The therapeutic limitation has been demonstrated in several clinical trials [5, 6]
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