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Activins are growth and differentiation factors which have been shown to have proliferative and antiproliferative actions in many tissues. In addition, they have been implicated in tumourigenesis in reproductive tissues. Although activin and inhibin are present in rat ventral prostate, inhibin beta, but not alpha, subunit proteins have been detected in the human prostate epithelial tumour cell lines LNCaP, DU145 and PC3. With this absence of capacity to produce inhibins, the aims of this study were to determine the effect of activin A and B and follistatin on DNA synthesis by these human prostate tumour cell lines. The results demonstrate a differential response to exogenously added activin A and B on DNA synthesis in vitro by the tumour cell lines. The inhibitory effects were observed on LNCaP cells in the absence or presence of stimulation with 1 nM 5 alpha-dihydrotestosterone and on the androgen-independent DU145 cells, but not the PC3 cells. Activin A caused a dose-dependent inhibition of DNA synthesis and proliferation by LNCaP and androgen-independent DU145 cells which was maximal at 8 ng/ml. The effect of exogenously added activin A was completely reversed by follistatin, but not by inhibin A. The addition of human recombinant FS 288 alone (400 ng/ml) did not have any effect on DNA synthesis, whereas inhibin A alone (400 ng/ml) caused a significant inhibition of DNA synthesis. The capacity of all three cell lines to produce activins and follistatins was demonstrated by the expression of the mRNAs and confirmed by the localisation of immunoreactivity for these ligands to the cytoplasm of the tumour cells. The growth inhibitory response to activins A and B by LNCaP and DU145 cells, and the ability of follistatin to block these effects, suggest that the autocrine interactions between activins and follistatins have a role in the regulation of LNCaP and DU145 prostate tumour cell growth.
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Fibroblast growth factors (FGFs) are a family of heparin binding proteins involved in many biological processes. These growth factors act through tyrosine kinase receptors (FGFRs); we have previously used immunohistochemistry to study FGFRs-1-4 in foetal, immature and adult rat testes, and found a discrete cell- and stage-specific localisation. Alternative mRNA splicing of FGFRs-1-3 leads to functional variants (IIIb and IIIc) with distinct ligand binding affinities, therefore we have identified the specific expression of functional FGFR variants and the expression and localisation of FGF ligands in testes from foetal, immature and adult rats. Using reverse transcriptase-polymerase chain reaction (RT-PCR), we found that mRNAs for FGFR-1 IIIb and IIIc, FGFR-2 IIIc, FGFR-3 IIIc and FGFR-4 were expressed in foetal, immature and adult testes. Ligands FGFs-1-5, and -8, which can signal through these receptors, were also expressed in testes at each age. Localisation of the ligands FGFs-1, -3 and -4 to rat testes by immunohistochemistry showed a discrete cell- and stage-specific localisation that altered during testis development. This study has shown that the ligands FGFs-1, -3 and -4 are expressed in the testis and have the capacity to signal through appropriate receptors that are also co-localised or expressed in adjacent cell types in the testis. Collectively, the expression profiles of the seven FGFR variants and FGFs-1-5 and -8 suggest a functional importance in testicular development and spermatogenesis. It is concluded that, future studies on the role of other FGF ligands, in particular FGFs-1-4, are warranted.
