PKC-dependent Regulation of NAG-1/PLAB/MIC-1 Expression in LNCaP Prostate Carcinoma Cells
نویسندگان
چکیده
NAG-1 (nonsteroidal anti-inflammatory drug-activated gene), a member of TGF beta superfamily, is involved in cellular processes such as inflammation, apoptosis/survival, and tumorigenesis and is regulated by p53, Sp1, and Egr-1. In the current study, the regulation of NAG-1 expression in LNCaP human prostate carcinoma cells by TPA (12O-tetradecanoylphorbol-13-acetate) was examined. TPA treatment increased NAG-1 protein and mRNA levels in a time and concentration-dependent manner as well as NF-κB binding/transcriptional activity in LNCaP cells. Pre-treatment with PKC (protein kinase C) inhibitor blocked TPAinduced increase in NAG-1 protein levels and NF-κB binding/transcriptional activity while an inhibition of p38, JNK, or MEK activity had no effect on TPA-induced NAG-1 levels and NF-κB transcriptional activity. Expression of constitutively active PKCs induced an increase in NF-κB transcriptional activity and NAG-1 protein levels in LNCaP cells. The expression of NF-κB p65 induced NAG-1 promoter activity and chromatin immunoprecipitaion assay for p65 showed that NF-κB binds NAG-1 promoter in LNCaP cells. Inhibition of TPA-induced NAG-1 expression by NAG-1 Si RNA blocked TPAinduced apoptosis in LNCaP cells, suggesting induction of NAG-1 negatively affects LNCaP cell survival. These results demonstrate that NAG-1 expression is up-regulated by TPA in LNCaP cells through a PKC-dependent pathway involving the activation of NF-κB.
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