A novel function of benzyl isothiocyanate in vascular smooth muscle cells: the role of ERK1/2, cell cycle regulation, and matrix metalloproteinase-9.
Dietary isothiocyanates (ITCs) have shown protective effects against certain chemically induced cancers in animal models. These inhibitory effects are associated with reduced levels of extracellular signal-regulated kinase (ERK) 1/2 activity and the arrest of the G(1) cell cycle. Benzyl isothiocyanate (BITC) treatment down-regulates cyclins and CDKs and up-regulates the expression of the CDK inhibitor p21, but up-regulation of p27 or p53 was not detected. Since antiatherogenic effects are not needed for antiproliferation, we determined whether BITC exerted inhibitory effects on matrix metalloproteinase-9 (MMP-9) activity in TNF-alpha-induced vascular smooth muscle cells (VSMCs). BITC inhibited TNF-alpha-induced MMP-9 secretion in VSMC in a dose dependent manner. This inhibition was characterized by the down-regulation of MMP-9, which is transcriptionally regulated at the NF-kappaB site, and the activation protein-1 (AP-1) site in the MMP-9 promoter. These findings indicate that BITC is an effective agent for inhibiting cell proliferation, the G1 to S phase cell cycle progress, and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC.
Lee
Jin-Young
JY
National Research Laboratory for Glycobiology and Department of Biochemistry and Molecular Biology, Dongguk University, Kyungju City, Kyungbuk, Korea.
Moon
Sung-Kwon
SK
Hwang
Cher-Won
CW
Nam
Kyung-Soo
KS
Kim
Yeon-Kye
YK
Yoon
Ho-Dong
HD
Kim
Min-Gon
MG
Kim
Cheorl-Ho
CH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D016213:Cyclins; D006131:Growth Inhibitors; D017879:Isothiocyanates; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C031403:benzyl isothiocyanate; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9