PI3K regulatory subunits and prostate cancer

该项目解决的中心问题是抑制磷脂酰肌醇3-激酶(PI3K)是否是治疗人类前列腺癌的合理方法。PI3K被认为与前列腺癌有关，因为最近发现PTEN/MMAC1抑癌基因编码一种磷酸酶，可以分解PI3K的脂类产物。PTEN基因缺失与高Gleason分级前列腺癌相关。缺乏PTEN的前列腺癌细胞系具有PI3K下游酶的结构性激活，包括AKT蛋白-丝氨酸/苏氨酸激酶，PTEN的重新引入(或添加PI3K抑制剂)阻断了这一途径，导致细胞减少和凋亡增加。尽管对细胞系的研究表明，抑制PI3K应该会抑制由于PTEN缺失而导致的肿瘤的生长和存活，但没有证据表明这在动物水平上是正确的。在这个项目中，我们打算测试PTEN缺失对小鼠前列腺癌发生的重要性。PTEN基因半合子的小鼠是存活的，并会发展成各种肿瘤，包括腺癌或前列腺癌。我们将删除PI3K的P85调节亚单位的基因，并确定这是否会损害PTEN+/-小鼠的前列腺癌发展。我们将协调这些研究与罗伯茨博士和塞勒斯博士的AIMS项目2和3，在这些项目中，PI3K催化亚单位和下游酶(AKT)的基因将在小鼠身上进行操作。前列腺特异性和受调控的PTEN基因和PI3K基因的缺失将使我们能够绕过这些基因种系丢失所导致的复杂性。来自不同小鼠模型的前列腺将被检查是否有增生和腺癌，并将被表征为PI3K途径中的酶的激活状态。此外，DNA微阵列将被用来研究因PI3K途径的激活或抑制而改变表达的基因簇。这些研究将提供对PI3K在前列腺癌发展中的作用的了解，评估激活这一途径的人类肿瘤的新方法，以及评估靶向PI3K催化或调节亚基用于前列腺癌化疗的有效性。

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.