PI3K/AKT is involved in mediating survival signals that rescue Ewing tumour cells from fibroblast growth factor 2-induced cell death

Br J Cancer. 2005 Feb 28;92(4):705-10. doi: 10.1038/sj.bjc.6602384.

Abstract

While in vitro studies had shown that fibroblast growth factor 2 (FGF2) can induce cell death in Ewing tumours, it remained unclear how Ewing tumour cells survive in vivo within a FGF2-rich microenvironment. Serum- and integrin-mediated survival signals were, therefore, studied in adherent monolayer and anchorage-independent colony cell cultures. In a panel of Ewing tumour cell lines, either adhesion to collagen or exposure to serum alone only had a minor protective effect against FGF2. However, both combined led to complete resistance to 5 ng ml(-1) FGF2 in three of four FGF2-sensitive cell lines (RD-ES, RM-82 and WE-68), and to an increased survival as compared to other culture conditions in TC-71 cells. Inhibition studies with LY294002 demonstrated that the serum signal is mediated via the phosphoinositide 3-OH kinase/AKT pathway. Thus, Ewing tumour cells escape FGF2-induced cell death by modulating FGF2 signalling. The tumour microenvironment provides the necessary survival signals by integrin-mediated adhesion and soluble serum factor(s). These survival signals warrant further investigation as a potential resistance mechanism to other apoptosis-inducing agents in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Neoplasms / metabolism*
  • Cell Death
  • Cell Line, Tumor
  • Cell Survival
  • Fibroblast Growth Factor 2 / metabolism*
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Sarcoma, Ewing / metabolism*
  • Signal Transduction

Substances

  • Proto-Oncogene Proteins
  • Fibroblast Growth Factor 2
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt