STEROID-GROWTH FACTOR INTERACTION IN HUMAN PROSTATE-CANCER .2. EFFECTS OF TRANSFORMING GROWTH-FACTORS ON ANDROGEN METABOLISM OF PROSTATE-CANCER CELLS

The ability of human prostate cancer cells to metabolize androgens was assessed through administration of physiological concentration (0.5-1 0 nM) of tritiated testosterone (T) as precursor and one-step analysis of both T degradation and products' formation by reverse-phase HPLC a nd on-line radioactive detection after either 24 h or 72 h incubation. Overall, different prostate cancer cells degraded T quire differently favoring alternatively reductive or oxidative metabolic pathways. In particular both LNCaP and DU145 cells retained high levels of unconver ted T, with a limited production of androstenedione and its 17-keto de rivatives and relatively high amounts of dihydrotestosterone (DHT) and 3 alpha-androstanediol (3 alpha-diol). in contrast, PC3 cells quickly degraded T and exhibited high formation rates of androstenedione and 17-keto metabolites, while neither dihydrotestosterone nor 3 alpha-dio l were detected after short or longer incubation rimes. The effects of both TGF alpha (50 ng/mL) and TGF beta(1) (5 ng/mL) on rates and dire ction of T metabolism were also explored. In LNCaP cells TGF alpha ind uced a significant (P < 0.04) decrease of the reductive metabolism of T with a corresponding enhancement of the oxidative pathway (P < 0.002 ), while TGF beta(1) did not significantly affect T metabolism. On the other hand, both reductive and oxidative pathways were only partially influenced by either growth factor in DU145 and PC3 cells, although T GF alpha significantly raised 5 alpha-androstanedione formation and re duced androsterone production in DU145 cells. All the above evidence w as confirmed at both 24 h and 72 h or using increasing doses of TGF al pha and TGF beta(1), a peak activity of 50 ng/mL and 5 ng/mL, respecti vely, being generally encountered Overall, our data suggest that TGFs may have a role in the growth regulation of hormone-responsive prostat e tumor cells through changes of the intracellular contents of biologi cally active androgen metabolites.