P13K P110BETA IN PROSTATE CANCER PROGRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 雄激素受体(AR)在前列腺癌的发生发展中起重要作用，但AR在前列腺癌细胞中反式激活的确切机制尚未完全阐明。很明显，对AR反式激活的更好理解将促进新策略的发展，这些策略可以干扰前列腺癌治疗的那些信号级联反应。 磷脂酰肌醇3-激酶(PI3K)是一种主要的细胞内信号分子。由于雄激素停药后PI3K信号转导靶点PTEN基因的失活突变(10号染色体上的磷酸酶和张力蛋白同源物缺失)以及其他未知机制，PI3K活性升高被认为是前列腺癌进展的主要机制之一。我们和其他人已经证明，PI3K活性对于雄激素诱导的前列腺癌细胞AR反式激活是不可或缺的。最有趣的是，在我们的初步研究中，我们发现PI3K p110β和p110伽马是AR反式激活所必需的，p110β的过表达而不是p110伽马的过表达诱导了前列腺癌细胞雄激素非依赖性AR的激活和细胞增殖。这些数据表明，PI3K p110β可能是AR反式激活和前列腺癌进展的关键因素。然而，目前尚不清楚PI3K p110β的表达是否与患者前列腺癌的进展有关。 这项科布雷项目奖提案的目标是(1)在一大群前列腺癌患者中检查PI3K p110β以及其他PI3K亚型的表达水平与疾病进展之间的相关性，以及(2)从大型库中确定先导化合物作为PI3K p110β的同型特异性抑制物。该项目奖将为NIH R01的应用奠定坚实的基础。NIH R01提案的长期目标是为前列腺癌干预开发新的治疗策略。中心假设是PI3K p110β活性的升高，由于异常表达或激活，增强了AR的反式激活，并促进了前列腺癌的疾病进展。该项目的基本原理是，它的成功完成将为NIH R01的应用奠定坚实的基础。最重要的是，这个项目的发现将极大地促进我们对前列腺癌进展机制的了解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer; however, the precise mechanisms of AR transactivation in prostate cancer cells are not fully illustrated. It is obvious that an improved understanding of AR transactivation will promote the development of novel strategies that disrupt those signaling cascades for prostate cancer treatment. Phosphatidylinositol 3-kinase (PI3K) is a major intracellular signaling molecule. Due to the inactivating mutation of PI3K signaling opponent PTEN gene (phosphatase and tensin homologue deleted on chromosome-10) and other unknown mechanism after androgen withdrawal, elevated PI3K activity has been proposed as one of the major mechanisms for prostate cancer progression. We and others have demonstrated that PI3K activity is indispensable for androgen-induced AR transactivation in prostate cancer cells. Most interestingly, in our preliminary studies, we found that PI3K p110beta and p110gamma are required for AR transactivation, and overexpression of p110beta but not p110gamma induced androgen-independent AR activation and cell proliferation in prostate cancer cells. These data suggest that PI3K p110beta may be a critical factor in AR transactivation and prostate cancer progression. However, it is not known if PI3K p110beta expression is correlated with prostate cancer progression in patients. The objectives of this COBRE Project Award proposal are (1) to examine the correlation between the expression levels of PI3K p110 beta, as well as other PI3K isoforms and disease progression in a large group of prostate cancer patients, and (2) to identify lead compounds from a large library as isoform-specific inhibitors for PI3K p110beta. This Project Award will build a solid foundation for a NIH R01 application. The long-term goal of the NIH R01 proposal is to develop novel therapeutic strategies for prostate cancer intervention. The central hypothesis is that elevated PI3K p110beta activity, due to aberrant expression or activation, enhances AR transactivation and promotes disease progression in prostate cancers.The rationale for this project is that its successful completion would build a strong and solid foundation of a NIH R01 application. Most importantly, the findings from this project will greatly advance our knowledge about mechanisms of prostate cancer progression.