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.
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