A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance
A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance
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DOI：
10.1158/1541-7786.mcr-10-0200
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发表时间：
2011-07-01
影响因子：
5.2
通讯作者：
Arcaro, Alexandre
中科院分区：
文献类型：
--
作者：
Guerreiro, Ana S.;Fattet, Sarah;Arcaro, Alexandre
髓母细胞瘤是儿童中最常见的恶性脑肿瘤，预后较差。我们有兴趣进一步了解靶向人类激酶组作为一种新的方法，使髓母细胞瘤化疗药物敏感的潜力。使用小干扰RNA（siRNA）文库下调髓母细胞瘤细胞系中已知的人类蛋白质和脂质激酶。在siRNA转染后，在存在或不存在低剂量顺铂的情况下，细胞增殖的分析确定了参与髓母细胞瘤化疗耐药性的新蛋白和脂质激酶。PLK1（polo-like kinase 1）被鉴定为参与髓母细胞瘤细胞系增殖的激酶。此外，包括ATR、LYK 5、MPP 2、PIK3CG、PIK4CA和WNK 4的一组6个基因被鉴定为有助于髓母细胞瘤细胞中的细胞增殖和对顺铂治疗的抗性。对原发性髓母细胞瘤肿瘤样品和细胞系中6种靶基因表达的分析揭示了LYK 5和PIK3CG的过表达。siRNA筛选的结果通过用特异性药理学抑制剂的靶向抑制来验证。p110 γ（由PIK3CG编码）的药理学抑制剂损害髓母细胞瘤细胞系中的细胞增殖，并使细胞对顺铂治疗敏感。总之，我们的数据表明，p110 γ磷酸肌醇3-激酶亚型是一个新的组合治疗髓母细胞瘤的目标。Mol Cancer Res; 9（7）; 925 - 35.（c）2011年《非洲标准化评论》。
Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110 gamma (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110 gamma phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma. Mol Cancer Res; 9(7); 925-35. (C)2011 AACR.