Key Role of Phosphoinositide 3-Kinase Class IB in Pancreatic Cancer
Key Role of Phosphoinositide 3-Kinase Class IB in Pancreatic Cancer
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DOI：
10.1158/1078-0432.ccr-10-1210
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发表时间：
2010-10-15
影响因子：
11.5
通讯作者：
Falasca, Marco
中科院分区：
文献类型：
--
作者：
Edling, Charlotte E.;Selvaggi, Federico;Falasca, Marco
目的：磷脂酰肌醇3-激酶(PI3K)信号转导通路在癌症中具有重要作用。到目前为止，大多数研究都集中在PI3K/p110α亚型上，已经发现它在几种不同的癌症中发生了突变。本研究的目的是确定哪些PI3K亚型参与胰腺癌(PDAC)，并研究这些亚型对胰腺癌细胞增殖、存活和诱导Akt激活的影响。实验设计：用免疫组织化学方法分析所有PI3K亚型及其下游靶点在人胰腺癌组织和正常胰腺癌组织中的表达。结果：免疫组织化学检测显示PI3K/p110γ亚型特异性高表达。评分显示72%的PDAC组织PI3K/p110γ染色阳性，而正常胰管组织中未见阳性染色。选择性抑制和siRNA下调PI3K/p110γ后的增殖分析表明，PI3K/p110γ是细胞增殖所必需的，而不是其他PI3K亚型。PI3K/p110γ的过表达确实增加了PDAC细胞系中的细胞数，并介导了Akt的激活。此外，通过溶血磷脂酸受体激活Akt需要PI3K/p110伽马。结论：这些数据首次证实了PI3K亚型p110伽马在人类癌症中的肿瘤特异性积累。此外，我们的结果表明PI3K/p110伽马在胰腺癌中的关键作用，我们假设PI3K/p110伽马的过度表达是疾病进展中的一个关键事件。临床癌症资源；16(20)；4928-37。(C)2010年AACR。
Purpose: Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110 alpha isoform, which has been found to be mutated in several different cancers. The aim of our study was to determine which specific PI3K isoforms are involved in pancreatic ductal adenocarcinoma (PDAC) and investigate the effects of these isoforms on proliferation, survival, and induction of Akt activation in pancreatic cancer cells.Experimental Design: The expression of all PI3K isoforms and downstream targets was analyzed by immunohistochemistry in human pancreatic cancer tissue and normal counterparts. Isoform selective inhibitors and short interfering RNA (siRNA) were employed to investigate the effects of the different PI3Ks on proliferation, survival, and intracellular signaling in PDAC cell lines.Results: Immunohistochemical screening revealed high specific expression of the PI3K/p110 gamma isoform. Scoring indicated that 72% of the PDAC tissue stained positive for PI3K/p110 gamma, whereas no stain was detected in normal pancreatic ducts. Proliferation analyses after selective inhibition and siRNA downregulation of PI3K/p110 gamma showed that PI3K/p110 gamma, but not other PI3K isoforms, was required for cell proliferation. Overexpression of PI3K/p110 gamma indeed increased cell numbers and mediated activation of Akt in PDAC cell lines. Moreover, PI3K/p110 gamma was required for Akt activation via lysophosphatidic acid receptors.Conclusions: These data represent the first identification of a tumor-specific accumulation of the PI3K isoform p110 gamma in human cancer. Further, our results signify a critical role for PI3K/p110 gamma in pancreatic cancer, and we hypothesize that PI3K/p110 gamma overexpression is a key event in the disease progression. Clin Cancer Res; 16(20); 4928-37. (C) 2010 AACR.