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

ROSA M. MARTÍN-OROZCO; CARMEN ALMARAZ-PRO; JAVIER RODRIGUEZ-UBREVA; M. ALICIA CORTÉS; SANTIAGO ROPERO; RAMÓN COLOMER; PILAR LÓPEZ-RUIZ; BEGOÑA COLÁS

NEOPLASIA

NEOPLASIA PRESS

Lugar: confirmar; Año: 2007 vol. 9 p. 614 - 624

1522-8002

Factor de impacto: 5,674 /Journal Ranking: Q1. The primary focus of this investigation was to studythe relationship between neuroendocrine (NE) differentiationand epidermal growth factor (EGF) becauseboth have been implicated in the progression of prostatecancer. For this purpose, we used gefitinib andtrastuzumab, which are inhibitors of EGF receptor (EGFR)and ErbB2, respectively. EGF prevents NE differentiationinduced by androgen depletion. This effect is preventedby gefitinib, which blocks the activation of EGFR andErbB2, stimulation of mitogen-activated protein kinase(MAPK), and cell proliferation induced by EGF. Conversely,trastuzumab does not inhibit the effect of EGFon EGFR phosphorylation, MAPK activity, cell proliferation,and NE differentiation, although it reduces ErbB2levels specifically, suggesting that ErbB2 is not necessaryto inhibit NE differentiation. Prevention of NE differentiationby EGF is mediated by a MAPK-dependentmechanismand requires constitutive Akt activation. Theabrogation of the PI3K/Akt pathway changes the role ofEGF from inhibitor to inductor of NE differentiation. Weshow that EGFR tyrosine kinase, MAPK, and PI3K inhibitorsinhibit the cell proliferation stimulated by EGFbut induce the acquisition of NE phenotype. Altogether,the present data should be borne in mind when designingnew clinical schedules for the treatment ofprostate cancer, including the use of ErbB receptorsand associated signaling pathway inhibitors.