The goal of this proposal is to uncover the molecular mechanisms by which the newly identified Akt1 S477/T479 phosphorylation contributes to Akt activation and tumorigenesis, as well as to examine whether specifically inhibiting the upstream kinases for this phosphorylation event such as Cdk2/Cyclin A could block prostate tumor growth. My long-term career goals are to apply the insights of molecular and cellular biology to understand the physiological significance of deregulated protein kinase activation that is important in the development of human malignancies, and to search for proper drugable kinase targets. Akt is observed to be hyperactivated in human cancers, which is associated with the hormone-resistant phenotype and a poor prognosis. The significance of the PI3K/Akt pathway in prostate cancer has made it an attractive target for the development of small molecular inhibitors. However, the application of Akt inhibitors met difficulties in clinical trials due to induction of apoptosis in both cancer cells and normal somatic cells. Thus, to achieve specific eradication of cancer cells, it is critical to pinpoint the signaling pathways that distinguish caner cells from normal cells. Our preliminary data showed that another cancer hallmark, Cdk2/Cyclin A, could directly phosphorylate Akt1 at S477/T479 in a cell cycle dependent manner to govern Akt activation, providing specific growth advantages for cancer cells. Thus we are aiming to examine the molecular mechanisms through which Akt1-pS477/pT479 phosphorylation facilitates Akt activation and whether inhibiting its upstream activation kinase, Cdk2/Cyclin A could specifically kill cancer cells. In this proposal, I plan to: 1) Elucidate the molecular mechanisms underlying cell cycle-dependent Akt activation; 2) Examine the role of of Akt1 S477/T479 phosphorylation in prostate tumorigenesis; 3) Determine whether targeted inhibition of Akt tail phosphorylation suppresses prostate cancer development through suppressing Akt activation. This K99/R00 award will provide protected time for me to pursue the hypotheses of this proposal, obtain new skill sets to execute experiments and solve problems. In addition, the award will also allow me to focus my efforts on independently conducting basic and translational research, and to train future young scientists. Should I receive this award, I will pursue this research in Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, where authorities in the fields of PI3 kinase signaling and prostate cancer research locate. The outcome of the proposed studies will help elucidate the detailed molecular mechanisms for Akt1-pS477/pT479 mediated Akt activation, provide evidence toward the rationale for using specific Cdk2/Cyclin A pharmacological intervention in personalized medicine for human cancers and deliver initial animal experimental results to test whether specifically targeting Cdk2/Cyclin A could retard prostate cancer progression in vivo.
Hyperactivation of the oncoprotein Akt is frequently observed in human cancers including prostate cancer. This proposal aims to elucidate a novel Akt phosphorylation event occurred at Akt carboxyl terminus (S477 and T479), which contributes to Akt activation and prostate tumorigenesis, as well as to examine whether inhibiting its upstream signaling components could be used as a new avenue of pharmacological intervention to treat prostate cancers with Akt hyperactivation.
