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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.IJ

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 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.

Authors+Show Affiliations

Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

14648701

Citation

Benini, Stefania, et al. "Contribution of MEK/MAPK and PI3-K Signaling Pathway to the Malignant Behavior of Ewing's Sarcoma Cells: Therapeutic Prospects." International Journal of Cancer, vol. 108, no. 3, 2004, pp. 358-66.
Benini S, Manara MC, Cerisano V, et al. Contribution of MEK/MAPK and PI3-K signaling pathway to the malignant behavior of Ewing's sarcoma cells: therapeutic prospects. Int J Cancer. 2004;108(3):358-66.
Benini, S., Manara, M. C., Cerisano, V., Perdichizzi, S., Strammiello, R., Serra, M., Picci, P., & Scotlandi, K. (2004). Contribution of MEK/MAPK and PI3-K signaling pathway to the malignant behavior of Ewing's sarcoma cells: therapeutic prospects. International Journal of Cancer, 108(3), 358-66.
Benini S, et al. 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. PubMed PMID: 14648701.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contribution of MEK/MAPK and PI3-K signaling pathway to the malignant behavior of Ewing's sarcoma cells: therapeutic prospects. AU - Benini,Stefania, AU - Manara,Maria Cristina, AU - Cerisano,Vanessa, AU - Perdichizzi,Stefania, AU - Strammiello,Rosaria, AU - Serra,Massimo, AU - Picci,Piero, AU - Scotlandi,Katia, PY - 2003/12/4/pubmed PY - 2004/1/24/medline PY - 2003/12/4/entrez SP - 358 EP - 66 JF - International journal of cancer JO - Int J Cancer VL - 108 IS - 3 N2 - 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. SN - 0020-7136 UR - https://www.unboundmedicine.com/medline/citation/14648701/Contribution_of_MEK/MAPK_and_PI3_K_signaling_pathway_to_the_malignant_behavior_of_Ewing's_sarcoma_cells:_therapeutic_prospects_ L2 - https://doi.org/10.1002/ijc.11576 DB - PRIME DP - Unbound Medicine ER -