This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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