Prostate cancer is a leading cause of death in American males, yet its molecular mechanisms are poorly understood. The proposed study approaches the question of the molecular mechanisms of prostate cancer from a novel, yet undeveloped angle, by studying the role of a newly discovered protein modification -- post-translational arginylation, which consists of the addition of arginine onto N-terminus of proteins. Our recent data demonstrates that arginylation is critical for the survival of an organism and that the knockout of the enzyme responsible for arginylation, ATE1, results in embryonic lethality in mice. Further, we found that the lack of protein arginylation results in perturbation of angiogenesis-- a process that is critical for tumor growth and metastases. Genomic analysis has identified a limited number of potential arginylation targets that are involved in regulation of oncogenic transformation and have been hypothesized to play a role in prostate cancer.
We propose to address the question of the role of protein arginylation in prostate cancer by studying the effect of ATE1 deletion in mouse prostate cancer models. We will develop a new mouse model system that combines the genetic deficiency in protein arginylation and the high occurrence of prostate tumors. We will then study prostate tumor occurrence, progression, and metastases in such mice and analyze cells derived from the prostate tumors in such mice. We will address the question whether the absence of protein arginylation and the resulting angiogenic defects observed in ATE1-/- mice lead to decreased prostate tumor occurrence, growth, and metastases. We will further use this model system to study the molecular mechanisms of prostate tumor progression that are affected by the defects of protein arginylation and identify protein targets that are important for prostate cancer progression and are regulated by protein arginylation. Finally, we will establish the potential of this model system for the development of new approaches to prostate cancer therapy.
This research is aimed at developing new insights into the molecular mechanisms and treatment of prostate cancer.