title: Steroid-growth factor interaction in human prostate cancer. 2. Effects of transforming growth factors on androgen metabolism of prostate cancer cells.
abstract: The ability of human prostate cancer cells to metabolize androgens was assessed through administration of physiological concentration (0.5-10 nM) of tritiated testosterone (T) as precursor and one-step analysis of both T degradation and products' formation by reverse-phase HPLC and on-line radioactive detection after either 24 h or 72 h incubation. Overall, different prostate cancer cells degraded T quite differently, favoring alternatively reductive or oxidative metabolic pathways. In particular, both LNCaP and DU145 cells retained high levels of unconverted T, with a limited production of androstenedione and its 17-keto derivatives 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-diol were detected after short or longer incubation times. The effects of both TGF alpha (50 ng/mL) and TGF beta 1 (5 ng/mL) on rates and direction of T metabolism were also explored. In LNCaP cells TGF alpha induced 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 TGF alpha significantly raised 5 alpha-androstanedione formation and reduced androsterone production in DU145 cells. All the above evidence was confirmed at both 24 h and 72 h or using increasing doses of TGF alpha and TGF beta 1, a peak activity of 50 ng/mL and 5 ng/mL, respectively, being generally encountered. Overall, our data suggest that TGFs may have a role in the growth regulation of hormone-responsive prostate tumor cells through changes of the intracellular contents of biologically active androgen metabolites.
authors.affiliation: Hormone Biochemistry Laboratories, School of Medicine, University of Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Carruba
authors.forename: O M
authors.initials: OM
authors.lastname: Granata
authors.forename: R
authors.initials: R
authors.lastname: Farruggio
authors.forename: S
authors.initials: S
authors.lastname: Cannella
authors.forename: A L
authors.initials: AL
authors.lastname: Bue
authors.forename: R E
authors.initials: RE
authors.lastname: Leake
authors.forename: M
authors.initials: M
authors.lastname: Pavone-Macaluso
authors.forename: L A
authors.initials: LA
authors.lastname: Castagnetta
mesh_terms: D000728:Androgens / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta