Estrogen-induced proliferation of urothelial cells is modulated by nerve growth factor.

Both nerve growth factor (NGF) and estrogen have been shown to stimulate proliferation of various cell types. Human urothelial cells (HUC) express the alpha- and beta-subtypes of the estrogen receptor (ER(alpha) and ER(beta)) as well as tyrosine kinase A (trkA), the high-affinity receptor for NGF. We investigated interactions between estrogen and NGF relative to cell proliferation using primary cultures of HUC. 17 beta-estradiol (E2) stimulated NGF synthesis by HUC, and E2 (50 nM), the ER(alpha) agonist 16 alpha-iodo-17 beta-estradiol (10 nM), or the ER(beta) agonist genistein (50 nM) each stimulated HUC proliferation, an effect that was abolished by the estrogen antagonist ICI-182,780 (100 nM). NGF (1-100 ng/ml) stimulated HUC proliferation, and this was abolished by NGF antiserum (0.1 microl/ml) or the trkA antagonist K252a (100 nM). HUC proliferation stimulated by E2 was also abolished by NGF antiserum or K252a. Finally, we observed that treatment of HUC with NGF (50 ng/ml) or E2 (50 nM) stimulated trkA phosphorylation, and this was abolished by K252a (100 nM) or NGF antiserum (0.1 microl/ml). These data indicate that the effects of ER activation on HUC proliferation at least partly involve activation of trkA by NGF.