title: Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.
abstract: Naringenin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative properties and the ability to induce apoptosis in hepatoma cell lines. However, there are no reports describing its effects on the invasion and metastasis of hepatoma cell lines, and the detailed molecular mechanisms of its effects are still unclear. In this study, we investigated the mechanisms underlying naringenin-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 (HepG2, Huh-7, and HA22T) and murine embryonic liver cells (BNL CL2). Naringenin suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κB (NF-κB) activity. It suppressed TPA-induced AP-1 activity through inhibiting the phosphorylation of the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and it suppressed TPA-induced inhibition of NF-κB nuclear translocation through IκB. Additionally, it suppressed TPA-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1. These data suggest that naringenin suppresses the invasiveness and metastatic potential of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways.
authors: Research Center for Traditional Chinese Medicine, Department of Medical Research, Taiwan; Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; Research Center for Chinese Medicine & Acupuncture, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors: Hung-Rong
authors: HR
authors: Yen
authors: Department of Chinese Medicine, Buddhist Dalin Tzu Chi General Hospital, Chia-Yi, Taiwan.
authors: Ching-Ju
authors: CJ
authors: Liu
authors: School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; Department of Chinese Medicine, Buddhist Dalin Tzu Chi General Hospital, Chia-Yi, Taiwan. Electronic address: yehcc0530@gmail.com.
authors: Chia-Chou
authors: CC
authors: Yeh
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D044950:Flavanones; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C005273:naringenin; D013755:Tetradecanoylphorbol Acetate
keywords: AKT; AP-1; ERK; JNK; NF-κB; PI3K