1. Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism.
- Author
-
Shim M and Eling TE
- Subjects
- 3' Untranslated Regions genetics, Antioxidants chemistry, Apoptosis drug effects, Blotting, Northern, Blotting, Western, Cell Nucleus metabolism, Cell Proliferation drug effects, Cytokines antagonists & inhibitors, Cytokines metabolism, Fluorescent Antibody Technique, Genes, jun physiology, Growth Differentiation Factor 15, Humans, Luciferases, MAP Kinase Kinase 6 antagonists & inhibitors, MAP Kinase Kinase 6 metabolism, MAP Kinase Kinase Kinases antagonists & inhibitors, MAP Kinase Kinase Kinases metabolism, Male, Promoter Regions, Genetic genetics, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, Protein Kinase C antagonists & inhibitors, Protein Kinase C metabolism, Protein Transport, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription, Genetic drug effects, Transfection, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases genetics, Antioxidants pharmacology, Cytokines genetics, Prostatic Neoplasms metabolism, Vitamin E pharmacology, p38 Mitogen-Activated Protein Kinases metabolism
- 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.
- Published
- 2008
- Full Text
- View/download PDF