Enhanced invasion of hormone refractory prostate cancer cells through hepatocyte growth factor (HGF) induction of urokinase-type plasminogen activator (u-PA)

Prostate. 2004 May 1;59(2):167-76. doi: 10.1002/pros.20009.

Abstract

Background: Increased expression of the hepatocyte growth factor (HGF) receptor (MET) is associated with high-grade prostatic adenocarcinoma and metastasis. However, the mechanism through which MET signaling contributes to prostate cancer (CaP) metastasis remains unclear.

Methods: Human PC-3 CaP cells and in vivo selected, isogeneic variant cells of increasing metastatic potential (PC-3M, PC-3M-Pro4, and PC-3M-LN4) were used to investigate the effect of HGF on CaP cell growth, protease production, and invasion. Cell-free urokinase-type plasminogen activator (u-PA) expression and function following HGF treatment were analyzed by Western blot, ELISA, and casein/plasminogen zymography. In vitro invasion stimulated by HGF was measured using Matrigel-coated invasion chambers.

Results: Both mRNA and functional protein for MET were detected in each of the CaP cell lines. HGF treatment (0-40 ng/ml) weakly increase proliferation, however, HGF induced soluble u-PA protein and activity 3-fold in the metastatic variant cells. HGF significantly stimulated the invasion of highly metastatic PC-3M-LN4 cells through Matrigel and treatment with specific urokinase receptor inhibitors diminished the HGF-stimulated invasion in a dose-dependent manner.

Conclusions: These results demonstrate the biological significance of u-PA up-regulation in response to HGF in highly metastatic hormone refractory CaP cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / pathology*
  • Antineoplastic Agents, Hormonal / pharmacology
  • Cell Division
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic*
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Male
  • Neoplasm Invasiveness / physiopathology*
  • Plasminogen Activators / pharmacology*
  • Prostatic Neoplasms / pathology*
  • Signal Transduction
  • Tumor Cells, Cultured
  • Up-Regulation
  • Urokinase-Type Plasminogen Activator / pharmacology*

Substances

  • Antineoplastic Agents, Hormonal
  • Hepatocyte Growth Factor
  • Plasminogen Activators
  • Urokinase-Type Plasminogen Activator