Androgen stimulates matrix metalloproteinase-2 expression in human prostate cancer.
Prostate growth and differentiation is androgen dependent, and increased expression of matrix metalloproteinase 2 (MMP-2) has been found in more aggressive prostate cancers. As part of our efforts to elucidate the mechanisms responsible for prostate cancer progression, we evaluated the MMP-2 expression after androgen stimulation in human prostate cancer LNCaP and LAPC-4 cells, which express a functional androgen receptor. Treatment of the cells with a synthetic androgen R1881 resulted in an increase of pro-MMP-2 expression assessed by Western blot and gelatinolytic zymography in both cell lines. R1881-stimulated pro-MMP-2 expression occurred in a dose-dependent manner, which was completely abrogated in the presence of the nonsteroid androgen antagonist bicalutamide. In accordance with the protein expression, MMP-2 promoter activity was also increased by R1881 in a cell-based luciferase reporter assay. However, R1881 treatment did not significantly affect either the pro-MMP-9 expression or its promoter activity. Although we observed an appearance of active form of MMP-2, its activator MT1-MMP was not changed after R1881 treatment. Pretreatment of the cells with inhibitors of RNA transcription, actinomycin D, or protein translation, cycloheximide, significantly suppressed R1881-induced pro-MMP-2 expression in LNCaP cells, indicating that androgen stimulates pro-MMP-2 gene expression. In addition, phosphatidylinositol 3'-kinase inhibitor, LY294002 or wortmannin, strongly inhibited R1881-induced pro-MMP-2 expression. Finally, R1881-enhanced LNCaP cell migration was clearly suppressed by LY294002 or the MMP-2 inhibitor OA-Hy in an in vitro migration assay. In conclusion, our data demonstrated that androgen stimulates pro-MMP-2 expression in LNCaP cells via phosphatidylinositol 3'-kinase-dependent androgen receptor transactivation.
Liao
Xinbo
X
Department of Urology, Kansas Cancer Institute, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Thrasher
J Brantley
JB
Pelling
Jill
J
Holzbeierlein
Jeffery
J
Sang
Qing-Xiang Amy
QX
Li
Benyi
B
D002465:Cell Movement / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D015741:Metribolone / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000503:physiopathology; D011944:Receptors, Androgen / Q000235:genetics; D045165:Testosterone Congeners / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured
D002867:Chromones; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D020778:Matrix Metalloproteinase 2; D061965:Matrix Metalloproteinase Inhibitors; D015741:Metribolone; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; D011944:Receptors, Androgen; D045165:Testosterone Congeners; C474031:N-hydroxy-9-octadecenamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one