Benzyl isothiocyanate inhibits metalloproteinase-2/-9 expression by suppressing the mitogen-activated protein kinase in SK-Hep1 human hepatoma cells.
Benzyl isothiocyanate (BITC) is a hydrolysis compound of glucotropaeolin in cruciferous vegetables. Many studies have reported that BITC prevents cancers in laboratory animals and might also be chemoprotective in humans. The purpose of this study was to investigate the effects of BITC on cell proliferation, metastasis, and MAPK pathways of SK-Hep1 human hepatocellular carcinoma cells. BITC suppressed SK-Hep1 cell proliferation in a dose-dependent manner, and exposure to 1 and 5 microM BITC reduced cell proliferation by 25% and 30%, respectively. The expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type-1/MMP (MT-1/MMP) is a known risk factor for metastatic disease. Gelatin zymography analysis revealed a significant downregulation of MMP-2/-9 protein expression in SK-Hep1 cells treated with 0.1-5 microM BITC. BITC treatment caused dose-dependent decreases in MMP-2/-9 and MT1-MMP mRNA levels as determined by RT-PCR. BITC also increased the mRNA levels of tissue inhibitors of matrix metalloproteinases-2 (TIMP-2) 1.3- and 1.5-fold after a 24 h exposure to 1 and 5 microM BITC, respectively. Increased TIMP-2 expression is mediated by the downregulation of MMP-2 and MT1-MMP. BITC inhibited the phosphorylation activities of all three major mitogen-activated protein kinases (MAPKs) in a dose-dependent manner. BITC at 5 microM reduced the ERK1/2 phosphorylation activity by 50% and p38 activity by 70%. BITC also reduced the p-JNK1/2 level by 30% and 70% at 1 and 5 microM treatments, respectively. These data may represent anti-metastatic activities of BITC through the suppression of MAPKs in SK-Hep1 cells.
Hwang
Eun-Sun
ES
Center for Agricultural Biomaterials, College of Agriculture and Life Sciences, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul 151-921, Republic of Korea.
Lee
Hyong Joo
HJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017879:Isothiocyanates; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; C031403:benzyl isothiocyanate; D020928:Mitogen-Activated Protein Kinases; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9