Contribution of MEK/MAPK and PI3-K signaling pathway to the malignant behavior of Ewing's sarcoma cells: therapeutic prospects

Int J Cancer. 2004 Jan 20;108(3):358-66. doi: 10.1002/ijc.11576.


Insulin-like growth factor receptor I (IGF-I)-mediated circuit is a major autocrine loop for Ewing's sarcoma (ES) cells and appears to be particularly important in the pathogenesis of this tumor. In this study, we analyzed the contribution of the 2 major pathways of the intracellular IGF-IR signaling cascade to the overall effects elicited by IGF-I in ES. Both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3-K) signaling pathways appeared to be constitutively activated in ES, likely due to the presence of the IGF-IR-mediated autocrine loop. We demonstrated that both MEK/MAPK (PD98059 or U0126) and PI3-K inhibitors (LY294002) profoundly impaired ES cell growth in monolayer and soft agar basal conditions. Both PD98059 and LY294002 inhibited ES cell cycle progression by inducing G1 blockage, whereas only LY294002 significantly affected the survival of ES cells. Exogenous IGF-I completely reverted LY294002-induced growth inhibition by abrogating antiproliferative and proapoptotic effects of the PI3-K inhibitor. By contrast, IGF-I could not rescue cells from growth inhibition induced by PD98059. MEK/MAPK blockade also significantly reduced the migratory ability of ES cells, both in basal and IGF-I-induced conditions, and increased chemosensitivity to doxorubicin, a leader drug in the treatment of ES patients. Our findings therefore identify MAPK pathway as a promising target for pharmacologic intervention in ES.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Bone Neoplasms / enzymology*
  • Bone Neoplasms / pathology
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Cell Movement / drug effects
  • Doxorubicin / pharmacology
  • Drug Combinations
  • Enzyme Inhibitors / pharmacology
  • Female
  • G1 Phase / drug effects
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Sarcoma, Ewing / enzymology*
  • Sarcoma, Ewing / pathology
  • Signal Transduction*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology


  • Antineoplastic Agents
  • Drug Combinations
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Insulin-Like Growth Factor I
  • Doxorubicin
  • Receptor, IGF Type 1
  • Mitogen-Activated Protein Kinase Kinases