Pathophysiological impact of targeting the ROS-p53 axis

Abstract: The goal of this PhD thesis was to define the importance of the interplay between reactive oxygen species (ROS) and their activation of the tumor suppressor p53 in development and disease. We addressed this question using molecular biology and biochemical techniques together with mouse genetics and bioinformatics. We have made two important discoveries: First, we show that antioxidant supplementation accelerates lung cancer progression in mice and the growth of human lung cancer cell lines. By reducing the levels of ROS and DNA damage, antioxidants deactivate the p53 protein and help cancer cells to evade growth arrest. Second, we show that the transcription factor zinc finger protein 148 (Zfp148) is a potent suppressor of p53 activation under oxidative conditions. During lung development, suppression of p53 prevents growth arrest of pulmonary cells and permits prenatal lung maturation. However, in the ApcMin/+ model of colorectal cancer and in the Apoe–/– model of atherosclerosis, suppression of p53 promotes tumor development and atherosclerosis, respectively. Thus Zfp148 suppression of p53 plays important roles in both physiological and pathological contexts. We conclude that: 1) Antioxidant supplementation may stimulate the growth and progression of undiagnosed lung tumors and should be used with caution. The risk of developing lung cancer in patients with chronic obstructive pulmonary disease (COPD) who take the antioxidant acetylcysteine to break down mucus should be carefully evaluated. 2) Therapeutic targeting of Zfp148 may have beneficial effects in cancer and atherosclerosis by increasing p53 activity.