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) differentiation and epidermal growth factor (EGF) because both have been implicated in the progression of prostate 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. Conversely, trastuzumab does not inhibit the effect of EGF on EGFR phosphorylation, MAPK activity, cell proliferation, and NE differentiation, although it reduces ErbB2 levels specifically, suggesting that ErbB2 is not necessary to inhibit NE differentiation. Prevention of NE differentiation 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 inhibitors inhibit the cell proliferation stimulated by EGF but induce the acquisition of NE phenotype. Altogether, the present data should be borne in mind when designing new clinical schedules for the treatment of prostate cancer, including the use of ErbB receptors and associated signaling pathway inhibitors.
Martín-Orozco
Rosa M
RM
Department of Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Madrid E-28871, Spain.
Almaraz-Pro
Carmén
C
Rodríguez-Ubreva
F Javier
FJ
Cortés
M Alicia
MA
Ropero
Santiago
S
Colomer
Ramón
R
López-Ruiz
Pilar
P
Colás
Begoña
B
D000230:Adenocarcinoma / Q000473:pathology*; D000728:Androgens; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D000077156:Gefitinib; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D000068878:Trastuzumab
D000728:Androgens; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016895:Culture Media, Serum-Free; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C494918:AKT1 protein, human