title: Vanillin Suppresses Cell Motility by Inhibiting STAT3-Mediated HIF-1α mRNA Expression in Malignant Melanoma Cells.
abstract: Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1α (HIF-1α) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1α protein accumulation and the transcripts of HIF-1α target genes related to cancer metastasis including fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), and urokinase plasminogen activator receptor (uPAR). It was also found that vanillin significantly suppresses HIF-1α mRNA expression and de novo HIF-1α protein synthesis. To understand the suppressive mechanism of vanillin on HIF-1α expression, chromatin immunoprecipitation was performed. Consequently, it was found that vanillin causes inhibition of promoter occupancy by signal transducer and activator of transcription 3 (STAT3), but not nuclear factor-κB (NF-κB), onHIF1A. Furthermore, an in vitro migration assay revealed that the motility of melanoma cells stimulated by hypoxia was attenuated by vanillin treatment. In conclusion, we demonstrate that vanillin might be a potential anti-metastatic agent that suppresses metastatic gene expression and migration activity under hypoxia via the STAT3-HIF-1α signaling pathway.
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Korea. peunji0503@kku.ac.kr.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Interdisciplinary Research Center for Health, Konkuk University, Chungju 380-701, Korea. yoonmilee@kku.ac.kr.
authors.forename: Yoon-Mi
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Korea. dk1050@kku.ac.kr.
authors.forename: Taek-In
authors.initials: TI
authors.lastname: Oh
authors.affiliation: Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases (SIRIC), Yonsei University College of Medicine, Seodamun-gu, Seoul 03722, Korea. BKIM2@yuhs.ac.
authors.forename: Byeong Mo
authors.initials: BM
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Korea. beongou@kku.ac.kr.
authors.forename: Beong-Ou
authors.initials: BO
authors.lastname: Lim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 380-701, Korea. jhlim@kku.ac.kr.|Interdisciplinary Research Center for Health, Konkuk University, Chungju 380-701, Korea. jhlim@kku.ac.kr.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Lim
mesh_terms: D001547:Benzaldehydes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D001547:Benzaldehydes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C100058:vanillin
keywords: HIF-1α; STAT3; melanoma; migration; vanillin