Lysophosphatidic acid-regulated mitogenic ERK signaling in androgen-insensitive prostate cancer PC-3 cells

Int J Cancer. 2002 Dec 20;102(6):572-9. doi: 10.1002/ijc.10734.


Advanced and recurrent prostate tumors contain elevated levels of activated extracellular signal-regulated kinases 1 and 2 (ERK) in comparison to early-stage or benign specimens, and inhibition of ERK activation attenuates growth factor-dependent proliferation of prostate cells, suggesting a potential regulatory role for ERK in prostate tumorigenesis. Factors responsible for ERK activation in prostate cells are not well defined. Here, we show positive cooperative interaction between the G protein-coupled lysophosphatidic acid (LPA) and tyrosine kinase epidermal growth factor (EGF) receptors in androgen-insensitive prostate cancer PC-3 cells. Pre-treatment of the PC-3 cells with LPA decreases the dose of EGF required to elicit maximal activation of EGFR. Furthermore, treatment with LPA alone induces the rapid (maximal signal within 2 min) tyrosine phosphorylation of EGFR, and subsequent (maximal signal after 5 min) activation of ERK, suggesting that EGFR activation precedes ERK phosphorylation and may constitute a required component for signal relay from the LPA receptor to ERK. Accordingly, we show that inhibition of EGFR kinase activity attenuates the LPA-regulated ERK activation. In addition, we find that the LPA-regulated tyrosine phosphorylation of EGFR and activation of ERK are attenuated by batimastat, a generic inhibitor of matrix metalloproteinases (MMP). However, unlike the situation in fibroblasts, we find that the LPA-induced transactivation of EGFR in PC-3 cells is not mediated by shedding of heparin-binding EGF. Together, our data show that LPA and EGF cooperate to induce mitogenic signaling in prostate cancer cells in an MMP-regulated activation of the ERK pathway.

Publication types

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

MeSH terms

  • Androgens / pharmacology
  • Enzyme Activation
  • ErbB Receptors / physiology
  • Humans
  • Lysophospholipids / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Matrix Metalloproteinases / physiology
  • Neoplasms, Hormone-Dependent / enzymology*
  • Neoplasms, Hormone-Dependent / pathology
  • Phosphorylation
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / pathology
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Tyrosine / metabolism


  • Androgens
  • Lysophospholipids
  • Tyrosine
  • ErbB Receptors
  • Matrix Metalloproteinases