Actinidia chinensis Planch root extract inhibits cholesterol metabolism in hepatocellular carcinoma through upregulation of PCSK9.
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.
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Mingyan
M
He
Clinical Science Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Jiayun
J
Hou
Clinical Science Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Lingyan
L
Wang
Clinical Science Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Minghuan
M
Zheng
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Tingting
T
Fang
Clinical Science Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Xiangdong
X
Wang
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.|Minhang Hospital, Fudan University, Shanghai, China.
Jinglin
J
Xia
D029042:Actinidia / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008954:Models, Biological; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry*; D000071449:Proprotein Convertase 9 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010936:Plant Extracts; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
PCSK9; cholesterol metabolism; hepatocellular carcinoma; root of Actinidia chinensis