Abstract 5809: eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells

Abstract

Abstract Redox balance is the critical liaison for cancer homeostasis. Moderate increases in reactive oxygen species (ROS) levels can lead to cancer formation and progression. However, a disproportional increase of ROS levels changes equilibrium in cell redox status and leads to cancer cell death. Therefore, exogenous agents or antioxidant inhibitors which augment ROS generation become a potential new way to target cancer cells. We have found excessive accumulation of cellular proteins during arginine starvation causes stresses on the endoplasmic reticulum (ER) protein folding machinery resulting in elevated ROS levels. In this study, we continue to examine that arginine starvation-attenuated heme oxygenase-1 (HO-1) translation exacerbates the high ROS level to kill the cancer cells. In addition, HO-1 translational downregulation is due to arginine starvation-induced O-GlcNAcylation of eIF2α at S219, T239, and T241 residues. Loss of O-GlcNAcylation at eIF2α significantly rescues arginine starvation-reduced HO-1 protein level, resulting in better recovery and migratory properties from starvation and lower ROS level. In addition, arginine starvation-induced O-GlcNAcylation of eIF2α to suppress HO-1 translation is independent of its phosphorylation at S51, which is another stress-stimuli modification that regulates eIF2 involved protein translation. Arginine starvation exploits O-GlcNAcylation to antagonize eIF2α phosphorylation-induced HO-1 expression. Taken together, arginine starvation is a potential anti-cancer therapy in which induced eIF2α O-GlcNAcylation presents itself as a critical role for metabolic adaptation and tumor growth by dysregulating the antioxidant protein in cancer cells. Citation Format: Yu-Wen Hung, Yi-Chang Wang, David K. Ann. eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5809.