title: Methyl-3-indolylacetate inhibits cancer cell invasion by targeting the MEK1/2-ERK1/2 signaling pathway.
abstract: Epidemiologic studies have suggested an inverse correlation between dietary intake of cruciferous vegetables and cancer risk. It is thus of interest to investigate the anticancer potential of phytochemicals presented in cruciferous vegetables. In this study, methyl-3-indolylacetate (MIA), a cruciferous indole for which the bioactivity has not been previously reported, was found to significantly suppress the invasion of cancer cells stimulated by the 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Our data show that MIA pretreatments inhibited matrix metalloproteinase 9 (MMP-9) expression in a concentration-dependent manner, resulting in decreased MMP-9 activity. By using real-time reverse transcription-PCR, luciferase reporter gene assay, and electrophoretic mobility shift assay, we provided convincing evidence that MIA suppresses MMP-9 gene transcription via targeting the activator protein-1 signaling but not the nuclear factor-kappaB pathway. The TPA-induced mitogen-activated protein kinase (MAPK) activation cascade was also analyzed. Despite extensive activation of major MAPKs [c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase-1/2 (ERK1/2)] under TPA stimulation, only the ERK1/2 activation and its consequent nuclear translocation were found to be diminished by MIA. Interestingly, MIA did not affect the TPA-induced phosphorylation of either c-Raf or MAPK/ERK kinase-1/2 (MEK1/2), two upstream kinases of ERK. Moreover, using the in vitro kinase assay, MIA was shown to inhibit the kinase activity of MEK1/2, the upstream kinases of ERK, suggesting that MEK is the major molecular target of MIA. In conclusion, data from this study provided new insight into the anticancer potential of MIA, a cruciferous vegetable-derived indole compound.
authors.affiliation: Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.forename: Ximei
authors.initials: X
authors.lastname: Wu
authors.forename: Qing
authors.initials: Q
authors.lastname: Huang
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.forename: Choon-Nam
authors.initials: CN
authors.lastname: Ong
mesh_terms: D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D007210:Indoleacetic Acids; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C520073:methyl-3-indolylacetate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate