Redox Modulation of Prostate Cancer

描述(申请人提供)：核因子kappaβ(核因子kB)，一种氧化还原敏感的转录因子，被公认为是促凋亡和促存活蛋白编码基因的调节因子。已有研究表明，激素非依赖性前列腺癌具有较高的核因子-kB组成水平，肿瘤治疗药物激活核因子-kB可钝化这些因子的活性，从而导致癌细胞死亡。该项目的目标是深入了解核因子-kB介导的导致固有辐射抵抗的机制，并确定可用于改善前列腺癌治疗的新方法。我们的初步数据表明，雄激素非依赖型前列腺癌具有高水平的特定核因子-kB家族成员及其存续的核因子-kB靶基因产物，包括主要抗氧化酶锰超氧化物歧化酶和抗凋亡蛋白BclXL。我们还发现，辐射诱导了核因子-kB的激活，呈两波模式。我们假设，高水平组成性核因子-kB的肿瘤细胞对抑制核因子-kB介导的细胞保护通路很敏感，调节这一通路可以改善侵袭性前列腺癌的放射反应。亲本PC-3及其核因子-kB突变衍生细胞系将被用作雄激素非依赖性前列腺癌细胞的模型。亲本LNCaP及其相应的衍生物将被用作雄激素依赖的前列腺癌细胞的模型。来自PC-3和LNCaP的前列腺癌细胞株的特性良好，将在体外和体内进行研究。五周大的雄性裸鼠将通过前列腺原位移植作为人类前列腺癌细胞的宿主。特异性目的1旨在确定在侵袭性前列腺癌细胞的高固有辐射抗性中起重要作用的核因子-kB家族的特定成员。特定目的2旨在测试选择性调节核因子-kB或基于氧化还原的干预可用于增强辐射敏感性的概念。特定目标3的设计是为了在实验治疗环境中验证特定目标2的结果。这项研究的完成将加深我们对核因子-kB家族成员参与细胞生存的机制的理解。这些信息可以作为发展选择性方法的基础，这些方法最终可能转化为显著的临床益处。

DESCRIPTION (provided by applicant): The nuclear factor kappa beta (NF-kB), a redox-sensitive transcription factor, is well established as a regulator of genes coding for both proapoptosis and prosurvival proteins. It has been shown that hormone-independent prostate cancer has a high constitutive level of NF-kB and activation of NF-kB by cancer therapeutic agents can blunt the activity of these agents to cause cancer cell death. The goal of this project is to gain insight into an NF-kB mediated mechanism leading to intrinsic radiation resistance and to identify novel approaches that can be used to improve the treatment of prostate cancer. Our initial data demonstrate that androgen-independent prostate cancer has high levels of selected members of the NF-kB family and its prosurvival NF-kB target gene products including the primary antioxidant enzyme, manganese superoxide dismutase, and the antiapoptotic protein, BclXL. We also found that radiation induced activation of NF-kB in a two-wave pattern. We hypothesize that tumor cells with high levels of constitutive NF-kB will be sensitive to inhibition of the NF-kB mediated cytoprotective pathway and modulation of this pathway can improve the radiation response of aggressive prostate cancer. Parental PC-3 and its NF-kB mutant derived cell lines will be used as models for androgen-independent prostate cancer cells. Parental LNCaP and its corresponding derivatives will be used as models for androgen-dependent prostate cancer cells. Well characterized PC-3 derived as well as LNCaP derived prostate cancer cell lines will be studied in vitro and in vivo. Five-weeks-old male athymic nude mice will be used as hosts of human prostate cancer cells by orthotopic implantation in the prostate glands. Specific aim 1 is designed to identify specific members of the NF-kB family that play an important role in high intrinsic radioresistance of aggressive prostate cancer cells. Specific aim 2 is designed to test the concept that selective modulation of NF-kB or redox-based intervention can be used to enhance radiation sensitivity. Specific aim 3 is designed to validate the results from Specific aim 2 in an experimental therapeutic setting. Accomplishment of this study will enhance our understanding of the mechanisms by which members of the NF-kB family participate in cell survival. This information can serve as a rationale for the development of selective approaches that might eventually translate into significant clinical benefit.