Studies of Normal and Neoplastic Prostate

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DESCRIPTION (provided by applicant): Over the years, we have focused on investigation of the fundamental functional biology of protein kinase CK2 with a specific view to its role in the pathobiology of prostate cancer. CK2 is a ubiquitous highly conserved multifunctional protein ser/thr kinase that has long been implicated in cell growth and proliferation. Its importance in cancer is emphasized by its deregulation in all the cancers that have been examined, including prostate cancer. Our paradigm-shifting discovery that CK2 can also suppress apoptosis suggests, for the first time, an important new link between CK2 and oncogenesis since deregulation of apoptosis (especially in prostate cancer) is a key feature of cancer phenotype. Our working hypothesis is that CK2 plays crucial roles in normal and abnormal prostatic growth control, and its deregulation is critically associated with oncogenesis through its impact on cell growth, apoptosis, and survival. Our long-term goals are to investigate the mechanisms involved in CK2 signaling in cell growth and suppression of apoptosis, and to exploit the key features of CK2 functional pathobiology in translational studies targeted to prostate cancer. To this end, we propose (a) to investigate the mechanisms involved in shuttling of CK2 to the nuclear matrix; (b) to examine the mechanisms by which CK2 suppresses apoptosis; (c), to exploit its downregulation as a potential therapeutic modality; and (d) to target its overexpression for generating a new transgenic mouse model of prostate cancer. In summary, our studies on CK2 functional biology with reference to prostate cancer biology represent an important and unique area of investigation. Also significant is the application of this knowledge to the development of a new transgenic mouse model and a new therapeutic modality for prostate cancer. The relevance of these studies is underscored by the fact that prostate cancer is a leading cause of cancer-related deaths in men in the U.S.A.