title: Modulation of the Tumor Metastatic Microenvironment and Multiple Signal Pathways by Prunella vulgaris in Human Hepatocellular Carcinoma.
abstract: Prunella vulgaris (PV) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat herpetic keratitis. In previous studies, PV was shown to suppress TPA-induced activation of MMP-9 and inhibit cell invasion and migration in hepatoma cell lines. However, the detailed molecular mechanism underlying these effects is still unclear. In this study, we investigated the mechanisms underlying PV-mediated inhibition of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (Huh-7 and HA22T). PV suppressed VEGF and MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) activity. PV suppressed TPA-induced AP-1 activity by inhibiting phosphorylation of the extracellular signal-related kinase (ERK), downregulating p38 signaling pathways, and suppressing TPA-induced inhibition of NF-[Formula: see text]B nuclear translocation through I[Formula: see text]B. PV suppressed TPA-induced activation of ERK/phosphatidylinositol-3-kinase/Akt upstream of NF-[Formula: see text]B and AP-1. These data suggest that PV modifies the metastatic microenvironment of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PV thus may have the therapeutic potential to inhibit the migration and invasion of HCC and act as potential agent for systemic therapies.
authors.affiliation: * Division of Hematology-Oncology, Department of Internal Medicine, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Su
authors.affiliation: ‡ School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: I-Hsin
authors.initials: IH
authors.lastname: Lin
authors.affiliation: † Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.
authors.forename: Yu-Miao
authors.initials: YM
authors.lastname: Siao
authors.affiliation: † Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.
authors.forename: Ching-Ju
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: † Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.|‡ School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Chia-Chou
authors.initials: CC
authors.lastname: Yeh
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D031347:Prunella / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9
keywords: AKT; AP-1; ERK; HCC; JNK; MMP-9; NF-B; PI3K; Prunella vulgaris; Tumor Invasion; VEGF