1α,25-dihydroxyvitamin D3 induced growth inhibition of PC-3 prostate cancer cells requires an active transforming growth factor beta signaling pathway

BACKGROUND. Prostate cancer growth inhibition by 1alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) is best characterized in the androgen dependent LNCaP cell line, where treatment with this hormone causes cell cycle arrest and apoptosis. 1,25(OH)(2)D-3 also inhibits the growth of PC-3 prostate cancer cells, but not through the induction of G, arrest or apoptosis. In this study, we have sought to elucidate the mechanism/s involved in PC-3 cell growth inhibition by 1,25(OH)(2)D-3. EXPERIMENTAL METHODS. We determined the effect of transforming growth factor beta (TGFbeta) blocking antibodies on 1,25(OH)(2)D-3 mediated growth inhibition of PC-3 cells. In addition, we also studied the effects of 1,25(OH)(2)D-3 on TGFbeta signaling and receptor expression. Finally, we assessed the role of TGFbeta signaling in the induction of the growth inhibitory protein, insulin like growth factor binding protein 3 (IGFBP-3), by 1,25(OH)(2)D-3. RESULTS. We find that 1,25(OH)(2)D-3 action in PC-3 cells is mediated through at least two distinct pathways, the TGFbeta pathway and the IGFBP-3 pathway. We show that 1,25(OH)(2)D-3 treatment elevates TGFbeta production and signaling, as well as receptor levels, in PC-3 cells. Further, using a blocking antibody against TGFbeta substantially reduces 1,25(OH)(2)D-3 mediated growth inhibition without affecting IGFBP-3 induction, suggesting that IGFBP-3, alone, is insufficient to inhibit the growth of PC-3 cells. (C) 2003 Wiley-Liss. Inc.