PI3K regulatory subunits and prostate cancer

该项目解决的中心问题是抑制磷酸肌醇3-激酶（PI 3 K）是否是治疗人类前列腺癌的合理方法。由于最近发现PTEN/MMAC 1肿瘤抑制基因编码水解PI 3 K脂质产物的磷酸酶，因此PI 3 K与前列腺癌有关。PTEN缺失与高Gleason分级前列腺肿瘤相关。缺乏PTEN的前列腺癌细胞系具有PI 3 K下游酶的组成性激活，包括AKT蛋白-Ser/Thr激酶，并且重新引入PTEN（或添加PI 3 K抑制剂）阻断该途径并导致细胞减少和细胞凋亡增加。虽然细胞系的研究表明，抑制PI 3 K应该抑制肿瘤的生长和生存，导致PTEN的损失，没有证据表明这是在动物水平上是正确的。在这个项目中，我们打算测试小鼠前列腺肿瘤发展中PTEN缺失的重要性。对于PTEN是半合子的小鼠是存活的并且发展各种肿瘤，包括腺癌或前列腺。我们将删除PI 3 K的p85调节亚基的基因，并确定这是否会损害PTEN+/-小鼠中前列腺肿瘤的发展。我们将协调这些研究与Roberts博士和Sellers博士的项目2和3的目标，其中PI 3 K催化亚基和下游酶（AKT）的基因将在小鼠中进行操作。前列腺特异性和调控的PTEN基因和PI 3 K基因缺失将使我们能够规避这些基因的生殖细胞丢失所导致的复杂性。将检查来自各种小鼠模型的前列腺的增生和腺癌，并将表征PI 3 K途径中酶的活化状态。此外，DNA微阵列将用于研究响应于PI 3 K通路的激活或抑制而改变表达的基因簇。这些研究将提供对PI 3 K在前列腺癌发展中的作用的理解，评估人类肿瘤激活该途径的新方法，以及评估靶向PI 3 K催化或调节亚基用于前列腺化疗的疗效。

The central question being addressed by this project is whether inhibition of phosphoinositide 3-kinase (PI3K) is a rational approach for treating human prostate cancers. PI3K has been implicated in prostate cancer because of the recent discovery that the PTEN/MMAC1 tumor suppressor gene encodes a phosphatase that hydrolyzes the lipid products of PI3K. Loss of PTEN correlates with high Gleason grade prostate tumors. Prostate cancer cell lines that lack PTEN have constitutive activation of enzymes downstream of PI3K, including the AKT protein-Ser/Thr kinase and reintroduction of PTEN (or addition of PI3K inhibitors) blocks this pathway and leads to decreased cell and increased apoptosis. Although studies with cell lines suggest that inhibition of PI3K should inhibit growth and survival of tumors that result from loss of PTEN, there is no evidence that this is true at the animal level. In this project, we intend to test the importance that result from loss of PTEN for prostate tumor development in mice. Mice that are hemizygotic for PTEN are viable and develop a variety of tumors, including adenocarcinoma or the prostate. We will delete genes for the p85 regulatory subunits of PI3K and determine whether this impairs prostate tumor development in the PTEN+/- mice. We will coordinate these studies with the aims Projects 2 and 3 by Dr. Roberts and Dr. Sellers where genes for the catalytic subunit of PI3K and for downstream enzymes (AKT) will be manipulated in mice. Prostate-specific and regulated deletion of the PTEN gene and the PI3K genes will allow us to circumvent complexities that result from germline loss of these genes. The prostates from the various mouse models will be examined for hyperplasia and adenocarcinomas and will be characterized for the activation state of enzymes in the PI3K pathway. In addition, DNA microarrays will be used to investigated gene clusters that change expression in response to activation or inhibition of the PI3K pathway. These studies will provide an understanding of the role of PI3K in prostate cancer development, new approaches for evaluating human tumors for activation of this pathway, and an assessment of the efficacy of targeting PI3K catalytic or regulatory subunits for prostate chemotherapy.