Regulation of growth hormone receptors in human prostate cancer cell lines.

We previously demonstrated the gene expression of two growth hormone (GH) receptor (GHR) isoforms in prostate cancer (PCa) patient tissues and human PCa cell lines. In that initial study, we characterized LNCaP cell GH binding characteristics to GHR and its activation of relevant signal transduction pathways. We now show that GH binding to GHR and GHR mRNA expression in the cell lines studied are hormonally regulated. In the androgen-dependent LNCaP cells, the potent, specific and stable androgen analogue, mibolerone, caused a time- and biphasic dose-dependent, stimulation of (125)I-hGH specific binding to cells cultured in serum-free medium (SFM); however, when LNCaP cells were grown in chemically defined Gc full medium, long-term mibolerone-induced inhibition was observed. This effect of Gc on the androgen response was mimicked by the triiodothyronine (T(3)) contained in GC. In contrast, oestradiol (E(2)), cortisol, and insulin-like growth factor (IGF)-I and -II all caused stimulation of GH binding. Furthermore, we also observed homologous and heterologous, isoform- and cell-type-specific regulation of GHR mRNA expression in all three cell lines. In LNCaP cells, GH caused stimulation of both GHR mRNA and of its exon 9-truncated isoform, GHR(tr); however, mibolerone, E(2) and T(3) all stimulated GHR(tr) mRNA more potently than they did GHR. In androgen-independent PC3 cells, GH stimulated GHR(tr) expression, but almost not GHR, while in contrast, in androgen-independent DU145 cells, GH caused a clear reduction in GHR and less so in GHR(tr). The differential regulation of GHR isoform gene expression in human PCa cell lines and of GHR functional capacity (GH binding), by hormones and growth factors relevant to disease progression, suggests that GHR may prove to be an additional therapeutic target to slow down/prevent progression of human prostate cancer.