Prostate Carcinogensis and PKC Signaling

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Although PKC isozymes have been generally viewed as growth- promoting proteins, phorbol esters, the most common PKC activators, cause growth inhibition or apoptosis in prostate cancer cells; suggesting that PKC isozymes may be important players in the control of growth and programmed cell death in these cells. The overall objective of this proposal is the evaluation of the roles of individual members of the PKC family as mediators of these responses, and the study of the signaling pathways involved in PKC function in prostate cancer cells. As an approach to overcome the lack of selectivity of pharmacological tools to study isozyme-selective function, we will deliver individual PKC isozymes into prostate cancer cells using adenoviruses. Using a PKCdelta adenovirus, we show strong preliminary evidence that this novel PKC isozyme is pro-apoptotic in androgen-sensitive LNCaP cells and induces G2/M arrest in androgen-independent cells. In Specific Aim 1 we will evaluate the role of individual PKC isozymes in cell growth and programmed cell death in prostate cancer cells. Since individual PKC isozymes may have either overlapping or distinct roles, a major goal of this proposal is to determine whether other members of the PKC family present in prostate cancer cells (PKCalpha, PKCepsilon, PKCnu, PKCdelta ) regulate cell growth or apoptosis. We will also characterize changes in the expression of cell cycle regulators that may accompany the G2/M arrest mediated by PKCdelta. In Specific Aim 2 we will characterize the signaling pathways involved in PKC-mediated apoptosis in prostate cancer cells, focusing on the MAPK cascades and survival signaling through the P13K/Akt pathway. This is relevant since many prostate tumors present mutations in PTEN, a negative regulator of the P13K pathway. In Specific Aim 3 we will evaluate whether overexpression of PKC isozymes in prostate cancer cells reduce their tumorigenic potential in athymic nude mice. In Specific Aim 4 we propose the generation of transgenic mice overexpressing PKC isozymes or their dominant negative forms in the prostate, using a novel Cre/loxP recombination system that allows constitutive expression of the transgene independent of the androgen levels. This model will allow for the evaluation of how expression of PKC isozymes regulate apoptosis and proliferation in the prostate after castration and androgen replacement, respectively. The outcome of these studies will be useful to determine whether PKC isozymes serve as potential targets for the therapeutics of prostate cancer. Our research will yield new insights into the molecular events of prostate carcinogenesis.