Induction of transforming growth factor-beta autocrine activity by all-trans-retinoic acid and 1 alpha,25-dihydroxyvitamin D3 in NRP-152 rat prostatic epithelial cells

Abstract

Retinoids and vitamin D analogues are known to inhibit the proliferation of a variety of cells in culture and prevent the formation of certain tumors in mammals. Although it is well established that these hormones control the transcription of many genes upon binding to and activating specific nuclear receptors, the mechanisms by which they prevent cancer are as yet poorly understood. In this study the role of the transforming growth factor-beta (TGF-beta) growth inhibitors, in promoting the biological activities of all-trans-retinoic acid (RA) and 1 alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) was studied in NRP-152 cells, a nontumorigenic epithelial line derived from rat dorsal-lateral prostate. Inhibition of growth by nanomolar concentrations of RA was associated with an increase in both mRNA and protein for all three TGF-beta isoforms, with greater and much earlier increases for TGF-beta s 2 and 3 (5.5 h) than for TGF-beta 1 (24 h). A monoclonal antibody against TGF-beta and TGF-beta 1 latency associated peptide (LAP), both of which neutralize all three TGF-beta isoforms, each block the ability of RA to inhibit growth of NRP-152 cells by > 95%. Neutralization of growth inhibition by isoform-specific antibodies suggested that all three TGF-beta s are involved in this effect. The ability of RA to upregulate fibronectin and thrombospondin expression in NRP-152 cells was also blocked by the monoclonal antibody. 1,25-(OH)2D3, which also induced TGF-beta s 2 and 3 but not TGF-beta 1, and their respective mRNAs, also induced fibronectin and thrombospondin through induction of TGF-beta. Thus, autocrine production of TGF-beta s may be a significant part of the mechanisms by which RA and 1,25-(OH)2D3 promote cellular differentiation.