c-jun-NH2JNK mediates invasive potential and EGFR activation by regulating the expression of HB-EGF in a urokinase-stimulated pathway

J Cell Biochem. 2008 Feb 15;103(3):986-93. doi: 10.1002/jcb.21469.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes / pharmacology
  • Autocrine Communication
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • Epidermal Growth Factor / physiology
  • ErbB Receptors / biosynthesis*
  • ErbB Receptors / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Male
  • Neoplasm Invasiveness
  • Phosphorylation / drug effects
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Up-Regulation
  • Urokinase-Type Plasminogen Activator / biosynthesis*
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / pharmacology

Substances

  • Anthracenes
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • pyrazolanthrone
  • Epidermal Growth Factor
  • ErbB Receptors
  • JNK Mitogen-Activated Protein Kinases
  • Urokinase-Type Plasminogen Activator