Rel B mediated-redox regulation of radiation therapy

描述（由申请人提供）：越来越多的数据表明，前列腺癌存在于氧化应激升高的状态，活性氧（ROS）对电离辐射（IR）的细胞毒性作用起着重要作用。然而，ROS也参与导致适应性反应的细胞信号传导过程，从而降低放射治疗的有效性。因此，尽管治疗技术进步迅速，但放射治疗的结果，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。我们已经确定了氧化还原敏感核因子κ β (NF-？B)是前列腺癌生长和发展的主要因素。初步数据表明：1)侵袭性前列腺癌具有较高的核内替代通路成员NF-:B和关键抗氧化酶锰超氧化物歧化酶（MnSOD）水平；2)抑制雄激素非依赖型侵袭性前列腺癌细胞中的RelB可导致肿瘤细胞中白细胞介素8 （IL8）水平降低，体内肿瘤生长减慢；3)在雄激素应答性前列腺癌细胞中过度表达RelB可促进肿瘤生长和IL8的产生，但降低前列腺特异性雄激素（PSA）的产生；4)抑制RelB核易位可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依赖的NF-？B开关激活前列腺癌细胞中IL8的表达，抑制PSA的表达。我们建议，除了采用标准的PSA测试外，复发性肿瘤生长的临床测试应包括测量il - 8水平。结合这些测试将提高癌症的准确检测和预后。为了验证这一假设，并验证联合使用il - 8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。目的1将利用生物化学和分子生物学方法阐明MnSOD调节RelB对前列腺癌细胞中il - 8和PSA转录的作用机制。目的2将研究il - 8在前列腺癌放射治疗中的保护作用。目的3将利用癌症患者的样本确定血清il - 8水平是否是前列腺癌对放射治疗反应的预测指标。这些基于机制的、从实验室到床边的方法应该为前列腺癌对放射治疗的抵抗机制提供新的见解，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。

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.