Targeting the PI3K p110α Isoform Inhibits Medulloblastoma Proliferation, Chemoresistance, and Migration
Targeting the PI3K p110α Isoform Inhibits Medulloblastoma Proliferation, Chemoresistance, and Migration
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DOI：
10.1158/1078-0432.ccr-08-0385
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发表时间：
2008-11-01
影响因子：
11.5
通讯作者：
Arcaro, Alexandre
中科院分区：
文献类型：
--
作者：
Guerreiro, Ana S.;Fattet, Sarah;Arcaro, Alexandre
目的：PI3K /Akt通路在人类肿瘤中频繁激活，在成神经管细胞瘤生物学中起重要作用。我们有兴趣进一步了解靶向PI3K/Akt信号作为一种新的髓母细胞瘤抗增殖方法的潜力。实验设计：研究I-A类PI3K亚型在成神经管细胞瘤样本和细胞系中的表达模式和功能。通过RNA干扰或抑制异构体特异性PI3K抑制剂下调p110 α、p110 β或p110 δ对细胞存活和下游信号传导的影响进行了分析。结果：与正常脑组织相比，在一组原发性髓母细胞瘤样本和细胞系中检测到催化p110 α亚型的过表达。通过RNA干扰下调p110 α表达可抑制成神经管细胞瘤细胞的生长，诱导细胞凋亡，降低细胞的迁移能力。这种作用是选择性的，因为靶向p110 β或p110 δ的RNA干扰不会导致类似的day细胞存活损伤。同种异构体特异性p110 α抑制剂也会损害成神经管细胞瘤细胞的增殖并使细胞对化疗敏感。用p110 α抑制剂处理的髓母细胞瘤细胞在肝细胞生长因子和胰岛素样生长因子- 1的刺激下进一步显示Akt和核糖体蛋白S6激酶的激活降低。结论：总之，我们的数据揭示了p110 α在成神经管细胞瘤生长和存活中的新功能。
Purpose: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in medulloblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in medulloblastoma.Experimental Design: The expression pattern and functions of class I-A PI3K isoforms were investigated in medulloblastoma turnout samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110 alpha, p110 beta, or p110 delta by means of RNA interference or inhibition with isoform-specific PI3K inhibitors.Results: Overexpression of the catalytic p110 alpha isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110 alpha expression by RNA interference impaired the growth of medulloblastoma cells, induced apoptosis, and led to decreased migratory capacity of the cells. This effect was selective, because RNA interference targeting of p110 beta or p110 delta did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110 alpha inhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110 alpha inhibitors further displayed reduced activation of Akt and the ribosomal protein S6 kinase in response to stimulation with hepatocyte growth factor and insulin-like growth factor-I.Conclusions: Together, our data reveal a novel function of p110 alpha in medulloblastoma growth and survival.