PROSTATE-CANCER CELL-GROWTH INHIBITION BY TAMOXIFEN IS ASSOCIATED WITH INHIBITION OF PROTEIN-KINASE-C AND INDUCTION OF P21(WAF1 CIP1)/

BACKGROUND. Inhibition of protein kinase C (PKC) and modulation of tra nsforming growth factor-beta (TGF-beta) are both associated with tamox ifen treatment, and both appear to be important in the regulation of p rostate cancer cell growth. Investigations were performed which sought to measure the efficacy, and to elucidate the mechanism of growth inh ibition by tamoxifen, in hormone-refractory prostate cancer. METHODS. Growth assays were performed on PC3, PC3-M, and DU145 prostate cancer cells. TGF-beta was measured by ELISA; p21(waf1/cip1) and retinoblasto ma (Rb) protein levels were measured by Western blot; PKC activity was measured by kinase assay; and effects upon cell cycle were measured b y flow cytometric analysis. RESULTS. IC(50)s for growth inhibition ran ged from 5.5-10 mu M, and were not affected by estrogen. Tamoxifen-med iated growth inhibition was not associated with induction of TGF-beta. However, tamoxifen treatment was associated with inhibition of PKC, w hich was followed by induction of p2l(waf1/cip1), Rb dephosphorylation , and G1/S phase cell cycle arrest. Similar effects were observed with the known PKC inhibitor, Ro31-8220. CONCLUSIONS. These data suggest t hat micromolar concentrations of tamoxifen inhibit prostate cancer cel l growth by inhibition of PKC, resulting in induction of the p21(waf1/ cip1) protein. Prostate 37:51-59, 1998. (C) 1998 Wiley-Liss, Inc.dagge r