Elevation of cyclic adenosine 3 ',5 '-monophosphate potentiates activationof mitogen-activated protein kinase by growth factors in LNCaP prostate cancer cells

Prostate cells are simultaneously exposed to a variety of peptide growth fa ctors and neuropeptides that elevate cAMP. Both the growth factors and cAMP have large effects on the growth, differentiation, and movement of many ce ll types. Because mitogen-activated protein kinase (;MAPK) is central to th ese effects, we analyzed the ways in which these agonists interact in regul ating MAPK in prostate cancer cells. We show that, in LNCaP prostate cancer cells, elevation of intracellular cAMP can potentiate the ability of epide rmal growth factor (EGF), interleukin 6, and serum to activate MAPK and tha t this potentiation depends on protein kinase A and Rap1, The response to c AMP is different in the androgen-independent prostate cancer cell line PC-3 , where elevation of cAMP slightly inhibits MAPK activation by EGF. We also show that treatment of LNCaP with the calcium ionophore A23187 or the phor bol ester phorbol 12-myristate 13-acetate activates MAPK, but the activatio n of MAPK by these agonists is inhibited rather than potentiated by increas ing cAMP, Finally, we show that phorbol 12-myristate 13-acetate and interle ukin 6 can potentiate the signaling activity of EGF, We conclude that neuro endocrine factors that elevate cAMP sensitize LNCaP prostate cancer cells t o signaling by peptide growth factors and that low levels of mixtures of gr owth factors can activate intracellular signaling to a greater degree than would be predicted from the activity of the individual agonists.