Rel B mediated-redox regulation of radiation therapy

Rel B 介导的放射治疗氧化还原调节

基本信息

批准号：
8600894
负责人：
DARET K ST CLAIR
金额：
$ 37.2万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/8600894
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 diagnosis cancer type cytotoxic cytotoxicity effective therapy follow-up improved in vivo inflammatory marker insight member men neoplastic cell novel outcome forecast overexpression prostate cancer cell public health relevance research clinical testing research study response signal processing treatment planning treatment strategy tumor tumor growth

项目摘要

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.

描述（由申请人提供）：积累的数据表明，前列腺癌存在于氧化应激的升高状态，并且活性氧（ROS）对电离辐射（IR）的细胞毒性作用有重要贡献。然而，ROS 也参与细胞信号传导过程，导致适应性反应，从而降低放射治疗的有效性。因此，尽管治疗技术取得了快速进步，但放射治疗的效果，特别是对于预后不良的肿瘤患者，仍有待改善。该项目的目标是确定新的机制，从而开发出有效治疗侵袭性前列腺癌的具体措施。我们已经确定氧化还原敏感核因子 kappa beta (NF-κB) 的替代途径是前列腺癌生长和进展的主要贡献者。初步数据表明：1）侵袭性前列腺癌具有较高的核RelB（NF-:B替代途径成员）和锰超氧化物歧化酶（MnSOD）（一种关键的抗氧化酶）水平； 2)抑制雄激素非依赖性侵袭性前列腺癌细胞中的RelB导致肿瘤细胞中白细胞介素8(IL8)水平降低并减少体内肿瘤生长； 3)雄激素反应性前列腺癌细胞中RelB的过度表达导致肿瘤生长和IL8产生增强，但前列腺特异性雄激素(PSA)产生减少； 4)抑制RelB核易位增强前列腺癌的放射敏感性。基于这些新颖且重要的初步发现，我们假设 RelB 通过 MnSOD 依赖性 NF-κB 开关来调节前列腺癌对辐射的反应，从而激活前列腺癌细胞中 IL8 的表达并抑制 PSA 的表达。我们建议，除了采用标准 PSA 测试之外，复发性肿瘤生长的临床测试还应包括测量 IL8 水平。结合这些测试将提高癌症检测和预后的准确度。为了检验这一假设并验证联合使用 IL8 和 PSA 作为预后因素的概念验证，将解决三个相互关联的具体目标。目标 1 将利用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。目标 2 将检查 IL8 在预防前列腺癌放射治疗效果中的作用。目标 3 将使用癌症患者的样本确定血清 IL8 水平是否是前列腺癌对放射治疗反应的预测标志物。这些基于机制的、从实验室到临床的方法应该为前列腺癌对放射治疗的耐药机制提供新的见解，并可能为前列腺癌的诊断、治疗计划和监测提供实用的预测措施。