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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115801-04
Application #
7843722
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Bernhard, Eric J
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$250,538
Indirect Cost
Name
University of Kentucky
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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

Showing the most recent 10 out of 13 publications