Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However, ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus, despite rapid advances in treatment techniques, the outcome of radiation therapy, especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-?B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that: 1) aggressive prostate cancers have high nuclear RelB, a member of the alternative pathway of NF-:B and manganese superoxide dismutase (MnSOD), a critical antioxidant enzyme levels;2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo;3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production;and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings, we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent, NF-?B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors, three interrelated specific aims will be addressed.
Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches.
Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer.
Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients. These mechanistic based, bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic, treatment planning and surveillance.

Public Health Relevance

Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus, this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA143428-02
Application #
8206511
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$387,406
Indirect Cost
$118,476
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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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
Schnell, David M; St Clair, Daret (2014) Redox pioneer: Professor Joe M. McCord. Antioxid Redox Signal 20:183-8
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
Jorgenson, Tonia C; Zhong, Weixiong; Oberley, Terry D (2013) Redox imbalance and biochemical changes in cancer. Cancer Res 73:6118-23
Miriyala, Sumitra; Holley, Aaron K; St Clair, Daret K (2011) Mitochondrial superoxide dismutase--signals of distinction. Anticancer Agents Med Chem 11:181-90