Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation.

Neuroendocrine (NE) differentiation in prostate cancer (PCa) has been found in some studies to correlate with unfavorable clinical outcome. The mechanisms by which PCa acquires NE properties are poorly understood. In this study, we demonstrate that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a prostate smooth muscle-derived mitogen and survival factor, can evoke NE differentiation in LNCaP human PCa cells. HB-EGF induction of NE differentiation was mediated by a mitogen-activated protein kinase (MAPK) kinase-dependent mechanism, and this process was blocked by p38 MAPK signaling. NE differentiation induced by HB-EGF occurred independently of STAT3 phosphorylation and coincided with continued cell cycle transit. These findings suggest that endogenous stroma-derived factors, acting through MAPK signaling pathways, may play a significant role in the acquisition of NE properties by PCa cells. They also demonstrate that withdrawal from the cell cycle is not a prerequisite for expression of NE characteristics by PCa.