title: Down-regulation of aldo-keto reductase AKR1B10 gene expression by a phorbol ester via the ERK/c-Jun signaling pathway.
abstract: AKR1B10 is a human member of the aldo-keto reductase (AKR) superfamily, and is considered to be a tumor biomarker because its expression is known to be significantly induced in the cells of various cancers such as lung non-small-cell carcinoma and hepatocellular carcinoma. However, the mechanisms underlying the regulation of its gene remain unclear. In the present study, we demonstrated that the phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA), down-regulated the expression of the AKR1B10 gene in the human lung cancer cell line, A549. The treatment of A549 cells with TPA for 24h significantly reduced the mRNA levels, protein levels, and promoter activity of AKR1B10 as well as the growth of A549 cells. TPA induced the phosphorylation of the MAP kinase, ERK, and U0126, an inhibitor of the MAP kinase kinase, MEK1, blocked the down-regulation of AKR1B10 by TPA, indicating that the MAP kinase ERK plays a role in regulating the expression of AKR1B10. TPA also induced c-jun gene expression in an ERK-dependent manner. The co-introduction of the c-Jun protein resulted in a decrease in the mRNA levels and promoter activity of AKR1B10 as well as A549 cell proliferation. These results suggested that the ERK/c-Jun signaling pathway may play an important role in the TPA-triggered down-regulation of AKR1B10 gene expression.
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan. Electronic address: nisinat@osaka-ohtani.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Nishinaka
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miura
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Sakou
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
authors.forename: Chiemi
authors.initials: C
authors.lastname: Hidaka
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Sasaoka
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Okamura
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmacy, Osaka-Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Terada
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics*; D000074408:Aldo-Keto Reductases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D010703:Phorbol Esters / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C554292:12-O-tetradecanoylphorbol-1,3-acetate; D010703:Phorbol Esters; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D013755:Tetradecanoylphorbol Acetate
keywords: AKR1B10; Aldo–keto reductase; Cancer; MAP kinase; TPA; U0126