Role of fibroblast growth factor receptor signaling in prostate cancer cell survival

J Natl Cancer Inst. 2001 Dec 5;93(23):1783-90. doi: 10.1093/jnci/93.23.1783.


Background: Expression of fibroblast growth factors (FGFs) is increased in a substantial fraction of human prostate cancers in vivo and in prostate cancer cell lines. Altered FGF signaling can potentially have a variety of effects, including stimulating cell proliferation and inhibiting cell death. To determine the biologic significance of altered FGF signaling in human prostate cancer, we disrupted signaling by expression of a dominant-negative (DN) FGF receptor in prostate cancer cell lines.

Methods: PC-3, LNCaP, and DU145 prostate cancer cells were stably transfected with DN FGFR constructs, and LNCaP and DU145 cells were infected with a recombinant adenovirus expressing DN FGFR-1. The effect of DN FGFR-1 expression was assessed by colony-formation assays, cell proliferation assays, flow cytometry, and cytogenetic analysis. Key regulators involved in the G(2)-to-M cell cycle transition were assessed by western blotting to examine cyclin B1 expression and by in vitro kinase assay to assess cdc2 kinase activity.

Results: Stable transfection of the DN FGFR-1 construct inhibited colony formation by more than 99% in all three cell lines. Infection of LNCaP and DU145 prostate cancer cells with adenovirus expressing DN FGFR-1 led to extensive cell death within 48 hours. Flow cytometry and cytogenetic analysis revealed that the DN FGFR-1 receptor led to arrest in the G(2) phase of the cell cycle before cell death. Cyclin B1 accumulated in DN FGFR-1-infected LNCaP cells, but cdc2 kinase activity was decreased.

Conclusions: These findings reveal an unexpected dependence of prostate cancer cells on FGF receptor signal transduction to traverse the G(2)/M checkpoint. The mechanism for the G(2) arrest is not clear. Our results raise the possibility that FGF-signaling antagonists might enhance the cell death induced by other prostate cancer therapies.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Blotting, Western
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle
  • Cell Death
  • Cell Division
  • Cell Survival
  • Chromosomes
  • Cyclin B / biosynthesis
  • Cyclin B1
  • Cytogenetics
  • Flow Cytometry
  • Genes, Dominant
  • Humans
  • Lac Operon
  • Male
  • Precipitin Tests
  • Prostatic Neoplasms / metabolism*
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Receptors, Fibroblast Growth Factor / physiology*
  • Signal Transduction*
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured


  • CCNB1 protein, human
  • Cyclin B
  • Cyclin B1
  • Receptors, Fibroblast Growth Factor
  • CDC2 Protein Kinase