Rel B mediated-redox regulation of radiation therapy

Rel B 介导的放射治疗氧化还原调节

• 批准号: 8028495
• 负责人: DARET K ST CLAIR
• 金额: $ 40.14万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028495
• 关键词: Address; Affinity Chromatography; Androgens; Animal Model; Antioxidants; Basic Science; Binding; Biochemical; Biological Assay; Cancer Center; Cancer Detection; Cancer Diagnostics; Cancer Etiology; Cancer Patient; Cancer Prognosis; Cessation of life; Clinical; Clinical Research; Cultured Cells; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Effectiveness; Enzymes; Family; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Human; Immunoprecipitation; Interleukin-8; Ionizing radiation; Kentucky; Lead; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Manganese Superoxide Dismutase; Measures; Mediating; Modeling; Molecular Biology; NF-kappa B; Nuclear; Nuclear Translocation; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Physicians; Play; Predictive Factor; Production; Prognostic Factor; Prostate; Prostate-Specific Antigen; Proteomics; Radiation; Radiation Tolerance; Radiation therapy; Reactive Oxygen Species; Recurrent tumor; Regulation; Resistance; Risk; Role; Sampling; Serum; Site-Directed Mutagenesis; Small Interfering RNA; Techniques; Testing; Time; Transcriptional Regulation; Translating; Tumorigenicity; Universities; Visit; base; bench to bedside; cancer cell; cancer diagnosis; cancer type; computerized data processing; cytotoxic; cytotoxicity; effective therapy; follow-up; improved; in vivo; inflammatory marker; insight; member; men; neoplastic cell; novel; outcome forecast; overexpression; research clinical testing; research study; response; treatment planning; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：累积数据表明前列腺癌存在于氧化应激状态升高，而活性氧（ROS）（ROS）对电离辐射（IR）的细胞毒性作用有重要贡献。但是，ROS还参与细胞信号传导过程，导致适应性反应，从而降低了放射治疗的有效性。因此，尽管治疗技术取得了迅速的进步，但放射治疗的结果，尤其是对于患有不利预后的肿瘤患者仍有待改进。该项目的目的是确定可能导致有效治疗侵略性前列腺癌的特定措施的新型机制。我们已经确定氧化还原敏感的核因子Kappa Beta（NF-？b）的替代途径是前列腺癌生长和进展的主要因素。初步数据表明：1）侵略性前列腺癌具有较高的核Relb，这是NF-：B和锰超氧化物歧化酶（MNSOD）的替代途径的成员，这是一种关键的抗氧化剂酶水平； 2）抑制雄激素独立攻击性前列腺癌细胞中RELB导致肿瘤细胞中白细胞介素8（IL8）水平降低，体内肿瘤的生长降低； 3）雄激素反应性前列腺癌细胞中RERB的过表达导致IL8的肿瘤生长和产生增强，但前列腺特异性雄激素（PSA）产生降低； 4）抑制RELB核易位会增强前列腺癌的辐射敏感性。基于这些新颖而重要的初步发现，我们假设RELB通过MNSOD依赖性调节前列腺癌对辐射的反应，NF-？B转换激活IL8表达并抑制PSA在前列腺癌细胞中的表达。我们建议，除了采用标准PSA测试外，还应测量复发性肿瘤生长的临床测试。结合这些测试将增强准确的癌症检测和预后。为了检验这一假设并验证IL8和PSA作为预后因素的综合使用的概念证明，将解决三个相互关联的特定目标。 AIM 1将通过生化和分子生物学方法阐明MNSOD调节RELB对前列腺癌细胞中IL8和PSA转录的影响的机制。 AIM 2将检查IL8在保护前列腺癌放射治疗的影响中的作用。 AIM 3将确定血清IL8水平是否是使用癌症患者的样品对放射治疗的预测标志物的预测标志。 这些基于机械的基础台至床边方法应提供对前列腺癌对放射疗法具有耐药性机制的新见解，并可能为前列腺癌诊断，治疗计划和监测提供实践预测措施。 公共卫生相关性：前列腺癌是男性中最常诊断的癌症，而死于前列腺癌的男性人数不可接受。从这项研究中获得的结果将提供有关白介素8（IL8）和前列腺特异性抗原（PSA）的新型机制的见解，并将测试使用其关系来预测辐射疗法治疗前列腺癌的功效的概念证明。因此，这项研究将使医生能够量身定制经风险调整的策略来治疗前列腺癌。