c-jun-NH2JNK mediates invasive potential and EGFR activation by regulating the expression of HB-EGF in a urokinase-stimulated pathway.
In this study, we demonstrated that tyrosine phosphorylation of EGFR and the autocrine expression of uPA and HB-EGF depend on the activity of c-jun amino-terminal kinase (JNK) in human prostatic DU-145 cells. These cells overexpress EGFR and produce a high amount of uPA. Treatment with either SP600125, a specific chemical inhibitor of JNK, or the expression of a dominant-negative JNK form inhibited autocrine production of uPA and HB-EGF, which block EGFR phosphorylation and mitigates invasive capacity. Our data provided evidence that in DU-145 cells, the maintenance of the activation level of EGFR, which determines the cellular invasive potential, operates through an autocrine loop involving the JNK-dependent production of uPA and HB-EGF activity. Moreover, we found that exogenously added uPA stimulates autocrine production of HB-EGF, and that blocking HB-EGF activity curbed DU-145 cell invasive potential.
Cáceres
Mónica
M
Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago, Chile.
Tobar
Nicolás
N
Guerrero
Javier
J
Smith
Patricio C
PC
Martínez
Jorge
J
D000873:Anthracenes / Q000494:pharmacology; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000502:physiology; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
D000873:Anthracenes; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C432165:pyrazolanthrone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator