CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway

Meng-Shian, Chen; Wang, Sheng-Fan; Hsu, Chih‐Yi; Yin, Pen-Hui; Yeh, Tien-Shun; Lee, Hsin Chen; Tseng, Ling‐Ming

doi:10.18632/oncotarget.23055

Cited by 218 publications

(187 citation statements)

References 48 publications

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“…ATF4 is involved in ferroptosis in cancer cells (Chen, Fan et al, 2017; Chen, Wang et al, 2017). We next detected ATF4 expression in hepatoma cells exposed to erastin.…”

Section: Resultsmentioning

confidence: 99%

“…In glioma cells, the silencing of ATF4 has been suggested as a solid strategy for impairing glioma growth and vasculature by sensitizing tumor cells to erastin‐ and RSL3‐induced ferroptosis (Chen, Fan et al, 2017). In breast cancer cells, knockdown of ATF4, on the contrary, prevented cystine starvation‐induced ferroptosis (Chen, Wang et al, 2017). Our present data demonstrated that miR‐214 suppressed ATF4 transcription and led to its protein reduction in HepG2 and Hep3B cells exposed to erastin.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

102

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Primary liver cancer is the second most frequent cause of cancer‐related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA‐214‐3p (miR‐214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR‐214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR‐214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre‐miR‐214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti‐miR‐214 sponge showed the opposite effect. Additionally, pre‐miR‐214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre‐miR‐214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR‐214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR‐214‐induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR‐214 elevated the ferroptosis‐promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis‐promoting effects of miR‐214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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“…ATF4 is involved in ferroptosis in cancer cells (Chen, Fan et al, 2017; Chen, Wang et al, 2017). We next detected ATF4 expression in hepatoma cells exposed to erastin.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

102

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“…The three related PanK genes encode pantothenate kinases, which are enzymes that control the ratelimiting step in CoA biosynthesis (21)(22)(23). CHAC1 (cation transport regulator homolog 1) encodes a stress-response protein that digests glutathione, regulating redox potential and enhancing ferroptosis (13,24). In addition to these p53 target genes, we examined the well-recognized ferroptosis biomarkers ALOX15 and ALOX12, which encode proteins that catalyze the peroxidation of polyunsaturated fatty acids to drive ferroptosis (11,25,26).…”

Section: Resultsmentioning

confidence: 99%

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

Leu

Murphy

George

2019

Proc. Natl. Acad. Sci. U.S.A.

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A population-restricted single-nucleotide coding region polymorphism (SNP) at codon 47 exists in the human TP53 gene (P47S, hereafter P47 and S47). In studies aimed at identifying functional differences between these variants, we found that the Africanspecific S47 variant associates with an impaired response to agents that induce the oxidative stress-dependent, nonapoptotic cell death process of ferroptosis. This phenotype is manifested as a greater resistance to glutamate-induced cytotoxicity in cultured cells as well as increased carbon tetrachloride-mediated liver damage in a mouse model. The differential ferroptotic responses associate with intracellular antioxidant differences between P47 and S47 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in S47 cells. Importantly, the disparate ferroptosis phenotypes related to the P47S polymorphism are reversible. Exogenous administration of CoA provides protection against ferroptosis in cultured mouse and human cells, as well as in a mouse model. The combined data support a positive role for p53 in ferroptosis and identify CoA as a regulator of this cell death process. Together, these findings provide mechanistic insight linking redox regulation of p53 to small molecule antioxidants and stress signaling pathways. They also identify potential therapeutic approaches to redox-related pathologies.p53 | coenzyme A | ferroptosis | S-thiolation | polymorphism

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“…CHAC 1 is the downstream of ATF4 and demonstrated to promote the degradation of GSH and the subsequent ferroptosis ( Figure 1). 5,50 PUMA is another downstream of ATF4 and is also up-regulated during the ER stress induced by the ferroptotic reagents, artemisinins (ART). However, PUMA activation will induce apoptotic cell death under the treatment of ferroptotic agents.…”

Section: Er In Ferroptosismentioning

confidence: 99%

Molecular mechanisms of ferroptosis and its role in cancer therapy

Ding

et al. 2019

J Cellular Molecular Medi

462

347

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Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron‐dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.

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CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway

Cited by 218 publications

References 48 publications

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

Molecular mechanisms of ferroptosis and its role in cancer therapy

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