The Role of NF-kappaB in Prostate Cancer Progression

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Despite advances in earlier disease detection and treatment modalities, prostate cancer (CAP) remains the second leading cause of death from malignancy among American men. Androgen ablation via castration causes acute regression; however, these tumors, via as yet undefined mechanisms, progress to an androgen-independent phenotype that is ultimately lethal for the patient. Commonly, NF-kB becomes constitutively in CaP through the loss of PTEN function. PTEN is a well characterized phosphatase and tumor suppressor that normally acts to suppress AKT mediated NF-kB activation. The main goal of this proposal is to determine the role(s) of specific NF-kB members in the regulating the general progression of CaP using both the pten+/- mouse and xenotransplanation based CaP model systems. This will be accomplished by: 1) determining the molecular roles of NF-kB and AR m regulating the transriptome, 2) characterizing NF-kB interactions with PSA and AR in modulating the transition from androgen-dependent to independent phenotype, and 3) investigating the effects of dominant negative or gene knockdown strategies targeting NF-kB members in the development, progression, and metasis of CaP. These studies are expected to provide evidence of NF-kB mediated CaP progression and the potential of inflammatory events to exacerbate and/or directly stimulate progression to an androgen-independent phenotype, as well as potentially elucidate an effective treatment for limiting CaP progression.