UROKINASE-MEDIATED EXTRACELLULAR-MATRIX DEGRADATION BY HUMAN PROSTATIC-CARCINOMA CELLS AND ITS INHIBITION BY RETINOIC ACID

Bath normal and malignant prostatic epithelial cells in culture secret e urokinase-type plasminogen activator (u-PA) into the culture medium, u-PA has been shown to have a direct association with invasive and me tastatic potential of many types of cancers, We propose that prostate cancer has the intrinsic ability to invade and metastasize because of its inherent ability to secrete the serine protease u-PA, We further p ropose that in prostate cancer, u-PA is the key enzyme which occupies a place at the apex of the proteolytic cascade and initiates the degra dative process, Subsequently, collagenases are recruited after activat ion of procollagenases by another serine protease plasmin formed by th e activation of plasminogen by u-PA, Extracellular proteolysis involvi ng plasmin can cause massive degradation of the extracellular matrix, We show that u-PA alone can use fibronectin as a substrate and degrade it, but u-PA alone did not degrade laminin, Serum-free conditioned me dium from DU-145 human prostatic carcinoma cells has the ability to de grade both fibronectin and laminin, However, treatment of cultures wit h 1 mu M all-trans retinoic acid (RA) for 48 h reduced the ability of serum-free conditioned medium to cause u-PA-mediated degradation of fi bronectin and laminin, Thus, RA had a protective effect on these extra cellular matrix glycoproteins, Treatment of cells with RA also decreas ed their ability to invade Matrigel in the in vitro invasion assay in a dose-dependent manner, RA at the 0.5, 1, and 10 mu M level reduced i nvasion to 65.7%, 46.7%, and 34.3% of control, respectively. RA reduce d extracellular proteolysis and thus inhibited extracellular matrix de gradation and invasion. These results may also explain one mechanism b y which retinoids inhibit invasion and metastasis in vitro and in vivo . These studies have important translational value in the chemoprevent ion of progression of prostatic intraepithelial neoplasia to invasive carcinoma.