EGF Prevents the Neuroendocrine Differentiation of LNCaP Cells Induced By Serum Deprivation: The Modulator Role of PI3K/Akt

The primary focus of this investigation was to study the relationship between neuroendocrine (NE) differ-entiation and epidermal growth factor (EGF) because both have been implicated in the progression of pros-tate cancer. For this purpose, we used gefitinib and trastuzumab,which are inhibitors of EGF receptor (EGFR) and ErbB2, respectively. EGF prevents NE differentiation induced by androgen depletion. This effect is prevented by gefitinib, which blocks the activation of EGFR and ErbB2, stimulation of mitogen-activated protein kinase (MAPK), and cell proliferation induced by EGF. Con-versely, trastuzumab does not inhibit the effect of EGF on EGFR phosphorylation, MAPK activity, cell prolifer-ation, and NE differentiation, although it reduces ErbB2 levels specifically, suggesting that ErbB2 is not neces-sary to inhibit NE differentiation. Prevention of NE dif-ferentiation by EGF is mediated by a MAPK-dependent mechanism and requires constitutive Akt activation. The abrogation of the PI3K/Akt pathway changes the role of EGF from inhibitor to inductor of NE differentiation. We show that EGFR tyrosine kinase, MAPK, and PI3K in-hibitors inhibit the cell proliferation stimulated by EGF but induce the acquisition of NE phenotype. Altogether, the present data should be borne in mind when de-signing new clinical schedules for the treatment of prostate cancer, including the use of ErbB receptors and associated signaling pathway inhibitors