This is a proposal to investigate the role of two regulatory proteins called IKK and NF-kappaB in the generation and progression of prostate cancer. We will also take advantage of the critical role of these proteins, once proven, to develop new strategies for treatment of prostate cancer. IKK is an enzyme (a protein kinase) that acts as a switch that causes NF-kappaB to move from the cytoplasm, where it is normally kept in cells that are not stimulated, to the nucleus, where it is present after cell stimulation. In the nucleus, NF-kappaB switches on the expression of genes, whose products act to enhance cell proliferation and suppress cell death. Normally this process is transient and is triggered only in response to certain stimuli, such as bacterial or viral infections. However, in many types of cancer, including prostate cancer, NF-kappaB becomes permanently turned on, such that it is continuously present in the nucleus. This will result in permanent or prolonged expression of genes that enhance cell proliferation and suppress cell death, altering the cellular status quo in a way that promotes the formation of tumors. In fact, the permanent suppression of programmed cell death (apoptosis), a process inherent to all normal cells, is one of the most important steps in the cascade of events that lead to tumor formation, as it contributes both to the emergence of tumors and to the protection of already formed tumors from anticancer drugs and radiation, which act by causing tumor cell death.

Our proposed research will first use a mouse model of prostate cancer and genetic manipulations that either increase or decrease the activity of the IKK enzyme. We will monitor the effect of these changes on tumor incidence, size, and appearance. These experiments will allow us to determine the role of IKK and NF-kappaB in the emergence of prostate cancer. Once the role of IKK in mouse prostate cancer is established, we will use various strategies to inhibit the activity of IKK components (IKK is a complex of several proteins) in human prostate cancer cell lines and determine the effect of these strategies on tumor cell proliferation, tumor cell survival, and the susceptibility of tumor cells to killing by anticancer drugs. We will also examine the effect of the IKK inhibitors on the proliferation and survival of human prostate cancer cells that have been transplanted into immunocompromised mice, in which they grow as distinct tumors.

In addition to providing critical and important information regarding the roles of IKK and NF-kappaB in prostate cancer, the successful completion of these studies may provide us with new strategies for the treatment of prostate cancer. For instance, inhibition of IKK may either lead to the spontaneous death of prostate cancer cells or greatly increase their susceptibility to killing by lower doses of conventional anticancer drugs, to which most prostate tumors are resistant.