Over the years, this program has made numerous fundamental contributions to the field of protein kinase CK2 functional biology in the context of prostate cancer. Developments in the field of CK2 have prompted the concept that CK2 serves as a master regulator in diverse functions in the cell. CK2 is dysregulated in all cancers including prostate cancer. Suppression of apoptosis by CK2, originally discovered by us, is regarded as one of its key functions as it provides a clear link of this kinase to the cancer cell phenotype. A focus of cancer therapeutics for more than a decade has been the development of therapies targeting protein kinases (PKs). PKs represent a large part of the genome involved in a multitude of key cellular functions. CK2 (formerly casein kinase 2 or II) is one such PK that has emerged as a significant target for cancer therapy, as originally proposed by us. Targeted cancer therapy has generally relied on single agent therapy; however, the emerging concept is that combinatorial therapy simultaneously targeting several downstream signals may be a more effective approach to eradicating the neoplastic disease. The focus of this research proposal is to investigate mechanisms of CK2 mediated regulation of cell survival and death which may lead to identification of additional targets for combinatorial therapy with anti-CK2 in various cancers. This research accords with the VA healthcare mission since prostate cancer is a major health issue in the veteran population and need for better management of this disease (and other cancers) remains critical. CK2 regulation of cell death and cell survival may occur at diverse levels; however, our recent observations suggest that mitochondrial machinery is a key locus of this function. One of the earliest responses of prostate cells to inhibition of CK2 is a change in mitochondrial membrane potential. Underlying mechanisms of how CK2 exerts its control on events leading to cell death or survival remain to be investigated. We propose two hypotheses: First, CK2 regulates intracellular Ca2+ signaling as the primary event to initiate activation of th executioner function of mitochondria (to be studied under Specific Aims 1 and 2). Second, increased CK2 expression levels influence mitochondrial function and activity as a mechanism of promoting cell survival. To address these hypotheses, we will undertake the following Specific Aims:
Specific Aim 1 is to investigate the role of CK2 in cellular dynamics of Ca2+, a key mediator of cell death.
Specific Aim 2 is to investigate mechanism(s) by which CK2 regulates Ca2+ signaling-related mitochondrial function involving cell death and survival, and determine the CK2 regulation of crosstalk between mitochondria and ER.
Specific Aim 3 is to determine the effects of increased CK2 expression levels on prostate cell mitochondrial function and activity. These comprehensive studies will significantly advance our knowledge on how CK2 functions in regulation of cell death and survival leading to a new paradigm in our understanding of CK2 function in cancer. Additionally, the data gained from completion of these studies will also yield potentially translatable information since CK2 is currently regarded as a cancer therapy target and there is also increasing interest in mitochondrial functions as targets of therapy. Identification of mitochondrial targets downstream of CK2 function would raise the potential of generating new combinatorial therapy approaches targeting cell death and survival machinery. The concepts and strategies proposed by us are original -elucidation of the mechanism(s) by which CK2 regulates cell death and survival will expand the fundamental knowledge on CK2 function in normal and disease state and potentially lead to identification of novel combinatorial therapeutic approaches in various cancers.
Protein kinase CK2, known to be elevated in all cancers that have been examined, is a potent suppressor of cell death and a key target for cancer therapy. The proposed investigation on the mechanisms by which CK2 regulates cell death and survival in prostate cancer will yield fundamental new knowledge on the function of this signal in normal and neoplastic prostate cells, and lead to identification of additional combinatorial targets for cancer therapy. Given the ubiquity of CK2 dysregulation in all cancers, the results obtained will have the strong potential o application to diverse cancers. The proposed research is of particular relevance to the VA research mission because cancer (especially prostate cancer) is a major health concern for the aging veteran population.
