Hypoxia-Mediated ATF4 Induction Promotes Survival in Detached Conditions in Metastatic Murine Mammary Cancer Cells

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 study was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in metastatic (metM-Wntlung) compared with nonmetastatic (M-Wnt) murine mammary cancer cell lines. We show that hypoxia induced a greater suppression of glutamine to glutamate conversion in metastatic cells (13% in metastatic cells compared to 7% in nonmetastatic cells). We also show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to nonmetastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. 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). Genetic depletion ATF4 demonstrated importance of this molecule for survival of hypoxic metastatic cells in detached conditions. These findings indicate that more aggressive, metastatic cancer cells utilize hypoxia for metabolic reprogramming and induction of antioxidant defense, including activation of ATF4, for survival in detached conditions.

Bacillus amyloliquefaciens attenuates the intestinal permeability, oxidative stress and endoplasmic reticulum stress: transcriptome and microbiome analyses in weaned piglets

“…GGT5 is confirmed to regulate immunity and OS ( Li et al, 2016 ). The change in GPT2 in murine mammary cancer cells expression was accompanied by the increase of the ATF4 ( Kiesel et al, 2022 ). SOD3 is also related to OS ( Wert et al, 2018 ).…”

Colorectal cancer and endoplasmic reticulum stress – potential targets for therapeutic compounds

“…The positive modulation of IRE1α induces the expression of XBP1, XBP1s and ERAD, further facilitating the survival of the malignant cell [21,37]. PERK activation via ARE, Keap1 and ATF4 may also favour the survival of neoplastic cells in hostile environments with nutrient deficiency, ATP shortage, ROS production and hypoxia [4,38].…”

“…NRF2 uses ARE and Keap1 to regulate the expression of genes responsible for modulating antioxidant enzymes, promoting the adaptation and survival of cancer cells. NRF2-Kelch-like ECH-associated protein 1 (NRF2-Keap1), as well as NRF2-ARE, can counteract the harmful effects of ROS on CRC cells and restore redox balance to favour neoplastic progression [38,56]. On the other hand, evidence shows that PERK can phosphorylate and facilitate the relocation and nuclear activity of FOXO (Forkhead box O), an important anti-tumour signaling of the PERKA pathway, also from the FOXO family of transcription factors, recognized as tumour suppressors that promote cell cycle arrest and apoptosis, in order to prevent the accumulation of genomic damage induced by genotoxic agents and oxidative stress.…”

Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis

“…ATF4 functions as a modulator of the cellular hypoxic response and contributes to the activation of genes that maintain normal endoplasmic reticulum function and facilitate survival 6 . ATF4 is involved in various pathophysiological processes, such as apoptosis, metabolism, antioxidant defence, tumourigenesis, and so on 7 . A recent study reported the physiological role of ATF4 in insulin secretion in response to glucose stimulation 8 .…”

“…6 ATF4 is involved in various pathophysiological processes, such as apoptosis, metabolism, antioxidant defence, tumourigenesis, and so on. 7 A recent study reported the physiological role of ATF4 in insulin secretion in response to glucose stimulation. 8 Importantly, ATF4 was down-regulated in high glucose-stimulated H9c2 cells and diabetic rat hearts.…”