Signal transduction-mediated regulation of urokinase gene expression in human prostate cancer.
Urokinase-type plasminogen activator (u-PA) contributes to tumor progression in prostate cancer (CaP). We have previously shown that u-PA expression is upregulated through the AP-1 and PEA3 sites and repressed by androgen. However, signaling pathways mediating u-PA gene expression in CaP are not delineated. We hypothesized that MAPK pathways mediate u-PA in CaP, and thereby studied specific ERK, JNK, and P38-MAPK pathway mutant constructs and inhibitors in vitro. Human, androgen insensitive CaP PC3 cells stably transfected with the androgen receptor expression vector and vector alone were used. A u-PA promoter CAT vector transiently expressed with dominant negative mutant signaling constructs was studied. All mutants drastically reduced u-PA promoter activity. Furthermore, inhibition of PI3K, an upstream regulator in the JNK/SAPK pathway, decreased u-PA promoter transcription. Collectively, these results show that MAPK pathways ERK, JNK/SAPK, and P38-MAPK represent a significant component in the regulation of u-PA expression in human CaP.
Eandi
J A
JA
Department of Urology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
Yang
J C
JC
Evans
C P
CP
D000728:Androgens / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics*
D000728:Androgens; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator