Accumulating evidence shows that deregulation of PI3K and PTEN signaling is important in human prostatecancers. However, the mechanisms of PI3K-induced and PTEN-inhibited prostate tumor growth are notknown. The long-term objectives of this proposal are to understand the molecular mechanisms of prostatetumorigenesis due to deregulation of the PI3K and PTEN pathway, and to elucidate the connection of PI3Kand PTEN downstream signaling components to tumor angiogenesis in vivo. We hypothesize that PI3Kregulates prostate tumorigenesis by inducing angiogenesis in the developing tumor and by activatingunexploited targets and mediators for inducing prostate tumorigenesis.
Specific Aim 1 is designed to identifythe mechanisms and new functions of PI3K and PTEN effectors that regulate prostate tumorigenesis usingour established tumor models.
This aim will study the effects of PI3K and PTEN in prostate tumor growth,test the role of angiogenesis in PI3K-induced tumor growth, and search for novel functions of PI3K effectorsinvolved in prostate tumor growth and angiogenesis.
Specific Aim 2 is designed to characterize PI3Kdownstream signaling molecules to transmit PI3K signals for inducing prostate tumor growth andangiogenesis. We will determine whether AKT transmits the oncogenic signals from the deregulation ofPI3K and PTEN signaling, and whether AKT in turn activates p70S6K1 and MDM2 in inducing prostatetumor angiogenesis in vivo. Since we found that MDM2 is upregulated by PI3K and AKT in cultured prostatecancer cells in our preliminary study, the study of MDM2 in PI3K- and AKT-induced prostate tumorigenesisand angiogenesis will help us to understand novel mechanisms of MDM2 expression in transmiting PI3K andAKT signals for inducing the tumor angiogenesis. This work will identify new functions of PI3K effectors inprostate tumorigenesis and angiogenesis, reveal mechanisms of PI3K signaling in regulating prostatetumorigenesis, and help to establish rational therapeutic strategies for human prostate cancer by targetingspecific signaling molecules in the future.
Showing the most recent 10 out of 30 publications
