The nuclear factor kappa beta (NF-kB), a redox-sensitive transcription factor, is well established as a regulator of genes coding for both proapoptosis and prosurvival proteins. It has been shown that hormone-independent prostate cancer has a high constitutive level of NF-kB and activation of NF-kB by cancer therapeutic agents can blunt the activity of these agents to cause cancer cell death. The goal of this project is to gain insight into an NF-kB mediated mechanism leading to intrinsic radiation resistance and to identify novel approaches that can be used to improve the treatment of prostate cancer. Our initial data demonstrate that androgen-independent prostate cancer has high levels of selected members of the NF-kB family and its prosurvival NF-kB target gene products including the primary antioxidant enzyme, manganese superoxide dismutase, and the antiapoptotic protein, BclXL. We also found that radiation induced activation of NF-kB in a two-wave pattern. We hypothesize that tumor cells with high levels of constitutive NF-kB will be sensitive to inhibition of the NF-kB mediated cytoprotective pathway and modulation of this pathway can improve the radiation response of aggressive prostate cancer. Parental PC-3 and its NF-kB mutant derived cell lines will be used as models for androgen-independent prostate cancer cells. Parental LNCaP and its corresponding derivatives will be used as models for androgen-dependent prostate cancer cells. Well characterized PC-3 derived as well as LNCaP derived prostate cancer cell lines will be studied in vitro and in vivo. Five-weeks-old male athymic nude mice will be used as hosts of human prostate cancer cells by orthotopic implantation in the prostate glands.
Specific aim 1 is designed to identify specific members of the NF-kB family that play an important role in high intrinsic radioresistance of aggressive prostate cancer cells.
Specific aim 2 is designed to test the concept that selective modulation of NF-kB or redox-based intervention can be used to enhance radiation sensitivity.
Specific aim 3 is designed to validate the results from Specific aim 2 in an experimental therapeutic setting. Accomplishment of this study will enhance our understanding of the mechanisms by which members of the NF-kB family participate in cell survival. This information can serve as a rationale for the development of selective approaches that might eventually translate into significant clinical benefit.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Bernhard, Eric J
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University of Kentucky
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Miao, Lu; Holley, Aaron K; Zhao, Yanming et al. (2014) Redox-mediated and ionizing-radiation-induced inflammatory mediators in prostate cancer development and treatment. Antioxid Redox Signal 20:1481-500
Xu, Yong; Fang, Fang; Miriyala, Sumitra et al. (2013) KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells. Cancer Res 73:4406-17
Miriyala, Sumitra; Holley, Aaron K; St Clair, Daret K (2011) Mitochondrial superoxide dismutase--signals of distinction. Anticancer Agents Med Chem 11:181-90
Sun, Yulan; St Clair, Daret K; Xu, Yong et al. (2010) A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells. Cancer Res 70:2880-90
Holley, Aaron K; Xu, Yong; St Clair, Daret K et al. (2010) RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells. Ann N Y Acad Sci 1201:129-36
Sinthupibulyakit, Chompunoot; Ittarat, Wanida; St Clair, William H et al. (2010) p53 Protects lung cancer cells against metabolic stress. Int J Oncol 37:1575-81
Shan, Weihua; Zhong, Weixiong; Zhao, Rui et al. (2010) Thioredoxin 1 as a subcellular biomarker of redox imbalance in human prostate cancer progression. Free Radic Biol Med 49:2078-87
Xu, Yong; Fang, Fang; Sun, Yulan et al. (2010) RelB-dependent differential radiosensitization effect of STI571 on prostate cancer cells. Mol Cancer Ther 9:803-12
Xu, Yong; Fang, Fang; Zhang, Jiayou et al. (2010) miR-17* suppresses tumorigenicity of prostate cancer by inhibiting mitochondrial antioxidant enzymes. PLoS One 5:e14356
Xu, Yong; Josson, Sajni; Fang, Fang et al. (2009) RelB enhances prostate cancer growth: implications for the role of the nuclear factor-kappaB alternative pathway in tumorigenicity. Cancer Res 69:3267-71

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