Abstract 1252: Arginylation as a new link between oxidative stress response and prostate cancer progression

Abstract

Abstract In this study, we evaluate the role of post-translational arginylation in prostate cancer, and introduce its potential as a biomarker of prostate cancer progression. Arginylation has not yet been studied in cancer. Our lab has observed Aringyltransferase (Ate1) is required for oxidative stress-mediated apoptosis. Our preliminary data in multiple eukaryotic cell models demonstrate that a downregulation of Ate1 increases resistance to oxidative stress, and elevated Ate1 is sufficient to induce cell death. Preliminary data mining shows that a downregulation of Ate1 correlates with a poorer prognosis in prostate cancer. Because prostate cancer cells produce a high amount of oxidative stress, the decrease of Ate1 likely increases their survival. We hypothesize that Ate1 is essential for the normal cellular response to insurmountable oxidative stress leading to apoptosis, and that a downregulation of Ate1 will promote cancer cell progression. We found that a loss of Ate1 in a nontumorigenic fibroblast cell line promotes spontaneous tumorigenicity within immunocompromised mice, a disruption of normal cell-cell interactions, and loss of contact inhibition. Also consistent with our hypothesis, prostate cancer cell line PC-3 with stably knocked down Ate1 exhibit higher invasiveness in the Boyden Chamber invasion assay, and higher resistance to H2O2-induced cell death during a 12-hour variable dose treatment. Similarly, the highly metastatic subpopulation of PC-3, PC3-ML, has naturally reduced Ate1 and exhibits higher invasiveness and resistance to H2O2. Finally, histological analysis of primary patient prostate cancer samples show a dramatic reduction of Ate1 compared to normal prostate tissue. These findings warrant further study of Ate1 as a metastasis suppressor, as well as a potential biomarker for prostate cancer progression. Citation Format: Fangliang Zhang, Michael D. Birnbaum, Akhilesh Kumar, William M. Morgan. Arginylation as a new link between oxidative stress response and prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1252. doi:10.1158/1538-7445.AM2015-1252