Guerreiro Ana S, Fattet Sarah, Fischer Barbara, Shalaby Tarek, Jackson Shaun P, Schoenwaelder Simone M, Grotzer Michael A, Delattre Olivier, Arcaro Alexandre
Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
Clin Cancer Res. 2008 Nov 1;14(21):6761-9. doi: 10.1158/1078-0432.CCR-08-0385.
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.
The expression pattern and functions of class I(A) PI3K isoforms were investigated in medulloblastoma tumour samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha, p110beta, or p110delta by means of RNA interference or inhibition with isoform-specific PI3K inhibitors.
Overexpression of the catalytic p110alpha isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110alpha 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 p110beta or p110delta did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110alpha inhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110alpha 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.
Together, our data reveal a novel function of p110alpha in medulloblastoma growth and survival.
磷酸肌醇3激酶（PI3K）/Akt信号通路在人类癌症中经常被激活，在髓母细胞瘤生物学中起关键作用。我们有兴趣进一步深入了解靶向PI3K/Akt信号作为髓母细胞瘤一种新型抗增殖方法的潜力。
在髓母细胞瘤肿瘤样本和细胞系中研究I（A）类PI3K亚型的表达模式和功能。通过RNA干扰或使用亚型特异性PI3K抑制剂抑制p110α、p110β或p110δ后，分析对细胞存活和下游信号传导的影响。
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性p110α亚型的过表达。通过RNA干扰下调p110α表达会损害髓母细胞瘤细胞的生长，诱导细胞凋亡，并导致细胞迁移能力下降。这种效应具有选择性，因为靶向p110β或p110δ的RNA干扰不会导致DAOY细胞存活受到类似损害。亚型特异性p110α抑制剂也会损害髓母细胞瘤细胞增殖，并使细胞对化疗敏感。用p110α抑制剂处理的髓母细胞瘤细胞在受到肝细胞生长因子和胰岛素样生长因子-I刺激后，Akt和核糖体蛋白S6激酶的激活进一步降低。
总之，我们的数据揭示了p110α在髓母细胞瘤生长和存活中的新功能。
