Abstract 6163: Integrated stress response contributes to triple negative breast cancer radioresistance by regulating glutathione biosynthesis

Abstract

Abstract Triple negative breast cancer (TNBC) is one of the most malignant gynecological cancer worldwide. Radiotherapy (RT) is an effective option for TNBC local control. However, TNBC tends to develop a radioresistant phenotype which results in a poor response of TNBC to following therapy. In this study, we identified integrated stress response (ISR) as the most activated signaling in radioresistant MDA-MB-231, MDA-MB-436, and MDA-MB-468 cells. We found that constitutive phosphorylation of eIF2α in radioresistant TNBC cells promoted the activation of activating transcription factor 4 (ATF4) via increasing its translational efficiency, which elicited the transcription of a set of genes implicated in GSH biosynthesis, including glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), and cystathionine-γ-lyase (CTH), leading to a higher intracellular level of reduced glutathione (GSH) and an efficient reactive oxygen species (ROS) scavenging after irradiation (IR). Treating radiosensitive TNBC cells with salubrinal, a selective inhibitor of eIF2α dephosphorylation, can mimic the stress-resistant phenotypes of their radioresistant counterparts. In contrast, eIF2α dephosphorylation or ATF4 knockdown accelerated IR-induced ROS accumulation and increased IR-induced cell apoptosis in radioresistant TNBC cells in vitro. In combination with eIF2α dephosphorylation, IR significantly reduced the size and weight of radioresistant TNBC xenograft tumors in vivo. These data reveal ISR as an important mechanism underlying TNBC radioresistance and provide a rationale for exploring eIF2 signaling as a novel therapeutic target for TNBC treatment. Citation Format: Xupeng Bai, Jie Ni, Yong Li, Julia Beretov. Integrated stress response contributes to triple negative breast cancer radioresistance by regulating glutathione biosynthesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6163.