Signal transduction-mediated regulation of urokinase gene expression in human prostate cancer

Urokinase-type plasminogen activator (u-PA) contributes to tumor progressio n in prostate cancer (CaP). We have previously shown that u-PA expression i s upregulated through the AP-1 and PEA3 sites and repressed by androgen. Ho wever, signaling pathways mediating u-PA gene expression in CaP are not del ineated. We hypothesized that MAPK pathways mediate u-PA in CaP, and thereb y studied specific ERK, JNK, and P38-MAPK pathway mutant constructs and inh ibitors in vitro. Human, androgen insensitive CaP PC3 cells stably transfec ted with the androgen receptor expression vector and vector alone were used . A u-PA promoter CAT vector transiently expressed with dominant negative m utant signaling constructs was studied. All mutants drastically reduced u-P A promoter activity. Furthermore, inhibition of PI3K, an upstream regulator in the JNK/SAPK pathway, decreased u-PA promoter transcription. Collective ly, these results show that MAPK pathways ERK, JNK/SAPK, and P38-MAPK repre sent a significant component in the regulation of u-PA expression in human CaP. (C) 2001 Academic Press.