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的升高状态，而活性氧物种(ROS)对电离辐射(IR)的细胞毒性效应起着重要作用。然而，ROS也参与细胞信号传递过程，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，但放射治疗的结果仍有待改善，特别是对预后不良的肿瘤患者。该项目的目标是确定可能导致制定有效治疗侵袭性前列腺癌的具体措施的新机制。我们发现氧化还原敏感型核因子kappaβ的另一种途径是前列腺癌生长和进展的主要因素。初步数据表明：1)侵袭性前列腺癌具有高水平的核RelB，这是核因子：B和锰超氧化物歧化酶(MnSOD)的替代途径之一，锰超氧化物歧化酶是关键的抗氧化酶水平；2)在雄激素非侵袭性前列腺癌细胞中抑制RelB导致肿瘤细胞中白介素8(IL8)水平的降低和体内肿瘤生长的抑制；3)在雄激素反应性前列腺癌细胞中过表达RelB导致肿瘤生长和IL8的产生增加，但前列腺特异性雄激素(PSA)的产生减少；以及4)抑制RelB核易位增强前列腺癌的辐射敏感性。基于这些新的和重要的初步发现，我们假设RelB通过依赖于MnSOD的核因子-βB开关来激活前列腺癌细胞中IL8的表达并抑制PSA的表达，从而调节前列腺癌对放射的反应。我们建议临床检测复发肿瘤生长时，除了使用标准的PSA检测外，还应测量IL8水平。将这些测试结合起来，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。目的1用生化和分子生物学方法阐明MnSOD调控RelB对前列腺癌细胞IL-8和PSA转录的影响机制。目的2研究IL8在前列腺癌放射治疗中的保护作用。目的3将使用癌症患者的样本来确定血清IL8水平是否可以预测前列腺癌对放射治疗的反应。这些机械性的、从工作台到床边的方法将为前列腺癌抵抗放射治疗的机制提供新的见解，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.