title: Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism.
abstract: NAG-1 (nonsteroidal anti-inflammatory drug-activated gene), a member of the transforming growth factor-beta superfamily, is involved in many cellular processes, such as inflammation, apoptosis/survival, and tumorigenesis. Vitamin E succinate (VES) is the succinate derivative of alpha-tocopherol and has antitumorigenic activity in a variety of cell culture and animal models. In the current study, the regulation and role of NAG-1 expression in PC-3 human prostate carcinoma cells by VES was examined. VES treatment induced growth arrest and apoptosis as well as an increase in NAG-1 protein and mRNA levels in a time- and concentration-dependent manner. VES treatment induced nuclear translocation and activation of p38 kinase. Pretreatment with p38 kinase inhibitor blocked the VES-induced increase in NAG-1 protein and mRNA levels, whereas an inhibition of protein kinase C, Akt, c-Jun NH(2)-terminal kinase, or MEK activity had no effect on VES-induced NAG-1 levels. Forced expression of constitutively active MKK6, an upstream kinase for p38, induced an increase in NAG-1 promoter activity, whereas p38 kinase inhibitor blocked MKK6-induced increase in NAG-1 promoter activity. VES treatment resulted in >3-fold increase in the half-life of NAG-1 mRNA in a p38 kinase-dependent manner and transient transfection experiment showed that VES stabilizes NAG-1 mRNA through AU-rich elements in 3'-untranslated region of NAG-1 mRNA. The inhibition of NAG-1 expression by small interfering RNA significantly blocked VES-induced poly(ADP-ribose) polymerase cleavage, suggesting that NAG-1 may play an important role in VES-induced apoptosis. These results indicate that VES-induced expression of NAG-1 mRNA/protein is regulated by transcriptional/post-transcriptional mechanism in a p38 kinase-dependent manner and NAG-1 can be chemopreventive/therapeutic target in prostate cancer.
authors.affiliation: Eicosanoids Biochemistry Section, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Minsub
authors.initials: M
authors.lastname: Shim
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eling
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D016758:Genes, jun / Q000502:physiology; D055436:Growth Differentiation Factor 15; D006801:Humans; D008156:Luciferases; D048669:MAP Kinase Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000975:Antioxidants; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D012333:RNA, Messenger; D014810:Vitamin E; D008156:Luciferases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human