P13K P110BETA IN PROSTATE CANCER PROGRESSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 雄激素受体（AR）在前列腺癌的发生和发展中起着至关重要的作用;然而，前列腺癌细胞中AR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破坏前列腺癌治疗的那些信号级联的新策略的开发。 磷脂酰肌醇3-激酶（PI 3 K）是一种重要的细胞内信号分子。由于雄激素戒断后PI 3 K信号传导的拮抗基因PTEN（10号染色体上的磷酸酶和张力蛋白同源物缺失）的失活突变和其他未知机制，PI 3 K活性升高已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，PI 3 K活性是不可缺少的雄激素诱导的AR在前列腺癌细胞的反式激活。最有趣的是，在我们的初步研究中，我们发现PI 3 K p110 beta和p110 gamma是AR反式激活所必需的，并且p110 beta而不是p110 gamma的过表达诱导了前列腺癌细胞中雄激素非依赖性AR激活和细胞增殖。这些数据表明，PI 3 K p110 β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PI 3 K p110 β的表达是否与患者的前列腺癌进展相关。 该COBRE项目奖提案的目的是（1）在一大群前列腺癌患者中检查PI 3 K p110 β表达水平以及其他PI 3 K亚型与疾病进展之间的相关性，以及（2）从大型库中鉴定先导化合物作为PI 3 K p110 β亚型特异性抑制剂。该项目奖将为NIH R 01申请奠定坚实的基础。NIH R 01提案的长期目标是为前列腺癌干预开发新的治疗策略。核心假设是，由于异常表达或激活，PI 3 K p110 β活性升高，增强AR反式激活，促进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 R 01的应用奠定坚实的基础。最重要的是，该项目的发现将大大推进我们对前列腺癌进展机制的认识。

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.