ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron

Abstract

Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H2O2 via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica, which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and H2O2. Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and H2O2 and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced H2O2 accumulation via upregulating NOX4 and SOD1 to generate H2O2 on one hand, and downregulating catalase and xCT to prevent H2O2 degradation on the other hand. H2O2 then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous H2O2 alone. Moreover, H2O2 reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H2O2 and iron.

Transcriptome Profiles of IncRNA and mRNA Highlight the Role of Ferroptosis in Chronic Neuropathic Pain With Memory Impairment

“…Increased endoplasmic reticulum stress is linked to ferroptosis, which upregulates the production of activated transcription factors (ATFs). Recent research has discovered that ATF3 can bind to the promoter of SLC7A11 , suppressing its expression and system Xc–transport function (which prevents lipid peroxidation and protects cells from nonapoptotic, iron-dependent death), resulting in reduced GSH production, increased free Fe 2+ , and lipid peroxidation accumulation, and ultimately causing DNA, protein, and lipid membrane damage ( Wang et al, 2020 ; Lu et al, 2021 ). Furthermore, ATF3 is a well-known marker of sensory neuron injury, with up-regulated expression found in the DRG and spinal cord in chronic pain models ( Ding et al, 2020 ; Wang K et al, 2021 ).…”

Nanoparticle delivery of miR-21-3p sensitizes melanoma to anti-PD-1 immunotherapy by promoting ferroptosis

“…ATF3 was reportedly a versatile transcriptional factor involved in multiple biological processes like cell death. [47][48][49][50] More importantly, as a common stress sensor, ATF3 could directly bind to the promoter of SLC7A11 to suppress its transcription and thereby result in lipid peroxidation and ferroptosis after the stimulation with erastin. 50 Consistent with previous reports, our data showed that both the mRNA and protein levels of ATF3 were significantly increased in response to either erastin/ RSL3 monotreatment, and were further upregulated after combined treatment with IFN-γ in melanoma cells (figure 7B,C).…”

“…[47][48][49][50] More importantly, as a common stress sensor, ATF3 could directly bind to the promoter of SLC7A11 to suppress its transcription and thereby result in lipid peroxidation and ferroptosis after the stimulation with erastin. 50 Consistent with previous reports, our data showed that both the mRNA and protein levels of ATF3 were significantly increased in response to either erastin/ RSL3 monotreatment, and were further upregulated after combined treatment with IFN-γ in melanoma cells (figure 7B,C). Chromatin immunoprecipitation assay showed more enrichment of ATF3 to the promoter of miR-21-3p on the treatment with erastin/RSL3, which was forwardly potentiated after combined treatment with IFN-γ (figure 7D).…”

Ferroptosis Signaling and Regulators in Atherosclerosis

“…Endoplasmic reticulum stress promotes the upregulation of ATF3, which increases intracellular H 2 O 2 levels through two pathways: ATF3 activates NOX4 transcription, overproduces of superoxide, inhibits SLC7A11 transcription, and deplets cysteine and GSH. H 2 O 2 increases intracellular Fe 2+ and restricts synthesis of GSH, leading to a continuous accumulation of toxic intracellular lipid peroxides ( Lu et al, 2021 ).…”