Endocrine Abstracts

Neuroendocrine molecules play a significant role in the progression of human prostate cancer (PCa) and its neuroendocrine differentiation has been associated to a worse prognosis. Among these molecules, the pleiotropic peptide neuropeptide Y (NPY) was found to be expressed in the human prostate and may show some relevance in PCa progression. In this study, we evaluated the direct effect of NPY on the growth of the human PCa cell lines LNCaP (androgen dependent) and DU145 and PC3 (androgen independent). The Y1-R subtype was found to be expressed in all PCa cell lines at the gene and protein level. Moreover, Y2-R and Y4-R genes were found to be expressed in PC3 cells and in LNCaP/DU145 cells, respectively. Treatment with 10⁻⁸ M NPY reduced the proliferation of LNCaP and DU145 cells and increased that of PC3 cells. The specific Y1-R antagonist BIBP3226 (10⁻⁶ M) abolished such effects, suggesting a mandatory role of Y1-R in this process. LNCaP cells showed elevated constitutive levels of phosphorylated extracellular kinase RK (ERK)1/2, which were not affected by NPY. In DU145 cells, treatment with 10⁻⁸ M NPY stimulated a long-lasting (>6 h) ERK1/2 phosphorylation, whereas, in PC3 cells, this effect was rapid, transient and mediated by protein kinase C, since it was abolished by pretreatment with the specific PKC inhibitor GF109203X (10⁻⁷ M). In DU145 and PC3 cells, NPY-induced ERK1/2 phosphorylation was prevented by a pretreatment with BIBP3226, further suggesting the involvement of Y1-R. Treatment with 10⁻⁸ M NPY reduced forskolin-stimulated cAMP accumulation only in PC3 cells, and did not change intracellular calcium concentration in any PCa cell line. Our data suggest that Y1-R activation by NPY represents an important regulator of the proliferation different PCa cell lines, with stimulatory or inhibitory effects depending on the peculiar intracellular signalling pattern activated in each clone.