Phosphorylation of mitogen-activated protein kinase is inhibited by calcitonin in DU145 prostate cancer cells

One of the causes of insensitivity to androgen ablation therapy in prostate cancer is thought to be attributable to elevated neuropeptides secreted by neuroendocrine cells in the tumor mass. Calcitonin (CT), one of these neur opeptides, is reported to be associated with the growth of prostate cancer. There is an increase in mitogen-activated protein (MAP) kinase activation as prostate cancer progresses to a more advanced and androgen-independent d isease. We examined the effect of CT on signal transduction and the relatio n between CT and early-response genes in the human androgen-insensitive pro state cancer cell line, DU145. The basal phosphorylation level of extracell ular signal-regulated kinase 1/2, which is a key kinase in the mediation of growth factor-induced mitogenesis in prostate cancer cells, was constituti vely up-regulated. N-[2-(4-bromocinnamyl) aminoethyl]-5-isoquinoline-sulfon amide (H89), a specific inhibitor of protein kinase A, potentiated the effe cts of more increased phosphorylation of extracellular signal-regulated kin ase 1/2. CT induced the inhibition of this MAP kinase phosphorylation, and this effect was completely abolished by pretreatment with H89. Our findings demonstrate that CT caused the inhibition of constitutive MAP kinase phosp horylation in a protein kinase A-dependent manner in DU145. The transient i ncrease of c-fos expression was detected after CT treatment, whereas expres sion of c-jun RNA was down-regulated after CT treatment. These results sugg est that CT may regulate early-response genes, c-jos and c-jun, via a MAP k inase cascade. In conclusion, these findings suggest that DU145 might be a useful model as a therapeutic approach of neuropeptides in ardrogen-indepen dent prostatic carcinoma.