title: Adenosine dialdehyde suppresses MMP-9-mediated invasion of cancer cells by blocking the Ras/Raf-1/ERK/AP-1 signaling pathway.
abstract: Adenosine dialdehyde (AdOx) inhibits transmethylation by the accumulation of S-adenosylhomocysteine (SAH), a negative feedback inhibitor of methylation, through the suppression of SAH hydrolase (SAHH). In this study, we aimed to determine the regulatory effect of AdOx on cancer invasion by using three different cell lines: MDA-MB-231, MCF-7, and U87. The invasive capacity of these cells in the presence (MCF-7) or absence (MDA-MB-231 and U87) of phorbal 12-myristate 13-acetate (PMA) was strongly decreased by AdOx treatment. Furthermore, the expression, secretion, and activation of matrix metalloproteinase (MMP)-9, a critical enzyme regulating cell invasion, in these cells were diminished by AdOx treatment. AdOx strongly suppressed AP-1-mediated luciferase activity and, in parallel, reduced the translocation of c-Fos and c-Jun into the nucleus. AdOx was shown to block a series of upstream AP-1 activation signaling complexes composed of extracellular signal-related kinase (ERK), mitogen-activated protein ERK kinase (MEK)1/2, Raf-1, and Ras, as assessed by measuring the levels of the phosphorylated and membrane-translocated forms. Furthermore, we found that suppression of SAHH by siRNA and 3-deazaadenosine, knock down of isoprenylcysteine carboxyl methyltransferase (ICMT), and treatment with SAH showed inhibitory patterns similar to those of AdOx. Therefore, our data suggest that AdOx is capable of targeting the methylation reaction regulated by SAHH and ICMT and subsequently downregulating MMP-9 expression and decreasing invasion of cancer cells through inhibition of the Ras/Raf-1/ERK/AP-1 pathway.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Jong Heon
authors.initials: JH
authors.lastname: Kim
authors.forename: Seung Cheol
authors.initials: SC
authors.lastname: Kim
authors.forename: Young-Su
authors.initials: YS
authors.lastname: Yi
authors.forename: Woo Seok
authors.initials: WS
authors.lastname: Yang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yang
authors.forename: Han Gyung
authors.initials: HG
authors.lastname: Kim
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011496:Protein Methyltransferases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014372:Tubercidin / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C018258:3-deazaadenosine; C027579:periodate-oxidized adenosine; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D019908:Proto-Oncogene Proteins c-raf; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins; C487181:ACSM3 protein, human; D003066:Coenzyme A Ligases; D000241:Adenosine; D014372:Tubercidin
keywords: AP-1; Adenosine dialdehyde; Isoprenyl carboxyl methyltransferase; Ras; S-adenosylhomocysteine hydrolase; Transmethylation