Abstract 2325: Hypoxia-mediated ATF4 induction promotes survival in detached conditions in metastatic murine mammary cancer cells

Abstract

Abstract Regions of hypoxia are common in solid tumors and drive changes in gene expression that increase risk of cancer metastasis. Tumor cells must respond to the stress of hypoxia by activating genes to modify cell metabolism and antioxidant response to improve survival. The goal of the current studies was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in non-metastatic M-Wnt compared to metastatic metM-Wntlung murine mammary cancer cell lines. We show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to non-metastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Further, hypoxia induces a greater suppression of glutamine to glutamate conversion in metastatic cells (15% in metastatic cells compared to 9% in non-metastatic cells). Interestingly, hypoxia increased the mRNA level of the transaminase glutamic pyruvic transaminase 2 (Gpt2, 7.7-fold) only in metM-Wntlung cells. The change in Gpt2 expression was accompanied by transcriptional (4.2-fold) and translational (6.5-fold) induction of the integrated stress response effector protein activating transcription factor 4 (ATF4), which mediated survival of hypoxic metastatic cells in detached conditions, as shown by genetic ATF4 depletion. These data indicate that more aggressive, metastatic cancer cells rely on metabolic reprogramming and induction of antioxidant defense, including activation of ATF4, in hypoxia for survival in detached conditions. Citation Format: Violet A. Kiesel, Stephen D. Hursting, Dorothy Teegarden. Hypoxia-mediated ATF4 induction promotes survival in detached conditions in metastatic murine mammary cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2325.