Abstract
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.
Copyright 2007 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anthracenes / pharmacology
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Autocrine Communication
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Cell Line, Tumor
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Cell Movement
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Cell Proliferation
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Enzyme Activation
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Epidermal Growth Factor / metabolism*
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Epidermal Growth Factor / physiology
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ErbB Receptors / biosynthesis*
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ErbB Receptors / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Heparin-binding EGF-like Growth Factor
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Male
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Neoplasm Invasiveness
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Phosphorylation / drug effects
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Kinase Inhibitors / pharmacology
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Up-Regulation
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Urokinase-Type Plasminogen Activator / biosynthesis*
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Urokinase-Type Plasminogen Activator / genetics
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Urokinase-Type Plasminogen Activator / pharmacology
Substances
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Anthracenes
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HBEGF protein, human
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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pyrazolanthrone
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Epidermal Growth Factor
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ErbB Receptors
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JNK Mitogen-Activated Protein Kinases
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Urokinase-Type Plasminogen Activator