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

被引:49
作者
Benini, S [1 ]
Manara, MC [1 ]
Cerisano, V [1 ]
Perdichizzi, S [1 ]
Strammiello, R [1 ]
Serra, M [1 ]
Picci, P [1 ]
Scotlandi, K [1 ]
机构
[1] Ist Ortoped Rizzoli, Lab Ric Oncol, I-40136 Bologna, Italy
关键词
Ewing's sarcoma; insulin-like growth factor I receptor; MAPK; PI3-K;
D O I
10.1002/ijc.11576
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 phosphatidyl-inositol-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. (C) 2003 Wiley-Liss, Inc.
引用
收藏
页码:358 / 366
页数:9
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