Peroxiredoxin 1 in radiotherapy of lung cancer

过氧化还原蛋白1在肺癌放射治疗中的应用

• 批准号: 7095240
• 负责人: YOUNG-MEE PARK
• 金额: $ 24.88万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095240
• 关键词: antineoplastics; antioxidants; apoptosis; cell proliferation; clinical research; free radical oxygen; gel mobility shift assay; gene expression; human tissue; lung neoplasms; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; neoplastic process; oxidation reduction reaction; oxidative stress; polymerase chain reaction; redoxin; site directed mutagenesis; transcription factor

DESCRIPTION (provided by applicant): Radiotherapy remains the major treatment modality for lung cancer. The therapeutic effect of radiation is primarily mediated by the generation of reactive oxygen species (ROS) and ROS-driven oxidative stress. Peroxiredoxins (Prxs) are an expanding family of antioxidant proteins. Prxs are expressed at high levels in all cells and constitute 0.1-0.8% of the soluble protein in mammalian cells. Two highly homologous members of this protein family, Prx1 and Prx2, have been shown to affect cell proliferation/apoptosis and increase the therapy resistance of cancer cells. Most studies to date have been restricted to observations of the elevated expression of Prxs in various cultured cell systems and some human tissues. However, the effects of Prx expression in human cancers, their influence on cancer therapy, and the regulatory basis for their expression in cancer have not been well investigated. The research proposed in this application emanates from our recent studies of Prx1 and Prx2 function and expression in human lung cancer. First, the expression profiles of Prx1 and Prx2 are clearly distinct in human lung cancer tissues. While Prx1 is significantly elevated in lung cancer cells, Prx2 is not and appears to be primarily expressed in the vascular endothelial cells of the tumor periphery. Second, we have found that the upstream regulatory regions of Prx1 and Prx2 display striking differences and that the levels of Prx1 message are much greater than of Prx2 in various human lung cancer cell lines. Thirdly, the expression of Prx1, but not Prx2, is up regulated at the message level in human lung cancer cells by oxidative stress-inducing conditions including exposure to ionizing radiation. Lastly, our studies have shown that over-expression of Prx1 in human lung cancer cells leads to an increase in clonogenic survival and a reduction in apoptosis in vitro following radiation treatment. These findings led us to postulate that Prx1 may possess unique functions and regulatory mechanisms in human lung cancer. Our hypothesis is that environmental and pathophysiological ROS and ROS-driven oxidative stress increase the level of Prx1 expression by activating redox-sensitive transcription factors and that Prx1 provides a cell survival advantage, in part by directly reducing ROS levels and oxidative damage and also by its ability to control the oxidation/function of redox-sensitive molecules that mediate cell proliferation/apoptosis. We propose 4 Specific Aims to test this hypothesis. In Aim 1, we will determine the functional consequences of Prx1 elevation and its potential role in the radiation resistance of human lung cancer. In Aim 2, we will investigate the regulatory mechanisms for the inducible regulation of Prx1 expression by radiation. In Aim 3, we will identify important redox-sensitive target/effector molecules that might mediate Prx1 function in response to radiation. In a translational extension of the above aims, we will test the predictive value of Prx1 in progression and therapy response of lung cancer in Aim 4 using human lung cancer specimen. In summary, the proposed research is highly translational in nature yet addresses important scientific questions on the role of Prx1 in the radiotherapy of lung cancer. These studies will define the role of Prx1 in the radiotherapy of lung cancer and provide a sound scientific basis upon which the regulation and function of Prx1 in lung cancer cell survival and radioresistance can be evaluated in lung cancer and other human malignancies.

描述（由申请人提供）：放射治疗仍然是肺癌的主要治疗方式。 放射的治疗作用主要通过活性氧（ROS）的产生和ROS驱动的氧化应激介导。 过氧化物酶（Peroxiredoxins，Prxs）是一个不断扩大的抗氧化蛋白家族。 Prx在所有细胞中以高水平表达，并且构成哺乳动物细胞中可溶性蛋白的0.1-0.8%。 该蛋白家族的两个高度同源的成员Prx 1和Prx 2已被证明影响细胞增殖/凋亡并增加癌细胞的治疗抗性。 迄今为止，大多数研究仅限于观察各种培养细胞系统和某些人体组织中Prxs表达的升高。 然而，Prx在人类癌症中表达的作用、它们对癌症治疗的影响以及它们在癌症中表达的调控基础尚未得到充分研究。 本申请中提出的研究源自我们最近对Prx 1和Prx 2在人肺癌中的功能和表达的研究。 首先，Prx 1和Prx 2的表达谱在人肺癌组织中明显不同。 虽然Prx 1在肺癌细胞中显著升高，但Prx 2不是并且似乎主要在肿瘤周边的血管内皮细胞中表达。 其次，我们发现Prx 1和Prx 2的上游调控区显示出显著的差异，并且在各种人肺癌细胞系中Prx 1的信息水平远高于Prx 2。 第三，Prx 1的表达，但不是Prx 2，在人肺癌细胞的信息水平上调氧化应激诱导条件，包括暴露于电离辐射。 最后，我们的研究表明，人肺癌细胞中Prx 1的过表达会导致放射治疗后体外克隆存活率增加和细胞凋亡减少。 这些发现使我们推测Prx 1可能在人类肺癌中具有独特的功能和调控机制。 我们的假设是，环境和病理生理活性氧和活性氧驱动的氧化应激通过激活氧化还原敏感性转录因子增加Prx 1的表达水平，Prx 1提供了细胞生存优势，部分是通过直接降低活性氧水平和氧化损伤，也通过其控制氧化还原敏感性分子介导细胞增殖/凋亡的氧化/功能的能力。 我们提出了四个具体目标来检验这一假设。 在目标1中，我们将确定Prx 1升高的功能后果及其在人肺癌放射抵抗中的潜在作用。 在目标2中，我们将研究辐射诱导调节Prx 1表达的调控机制。 在目标3中，我们将确定重要的氧化还原敏感的目标/效应分子，可能介导Prx 1功能响应辐射。 在上述目标的翻译延伸中，我们将使用人肺癌标本测试目标4中Prx 1在肺癌进展和治疗反应中的预测价值。 总之，拟议的研究在本质上是高度转化的，但解决了关于Prx 1在肺癌放射治疗中的作用的重要科学问题。 这些研究将明确Prx 1在肺癌放射治疗中的作用，并为评估肺癌和其他人类恶性肿瘤中Prx 1在肺癌细胞存活和放射抗性中的调节和功能提供可靠的科学依据。