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

Stefania Benini, Maria Cristina Manara, Vanessa Cerisano, Stefania Perdichizzi, Rosaria Strammiello, Massimo Serra, Piero Picci, Katia Scotlandi

Research output: Contribution to journalArticlepeer-review

Abstract

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 G I 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.

Original languageEnglish
Pages (from-to)358-366
Number of pages9
JournalInternational Journal of Cancer
Volume108
Issue number3
DOIs
Publication statusPublished - Jan 20 2004

Keywords

  • Ewing's sarcoma
  • Insulin-like growth factor I receptor
  • MAPK
  • PI3-K

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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