Abstract
Activating transcription factor 4 (ATF4), a member of the ATF/cAMP response element-binding (CREB) family, plays a critical role as a stress-induced transcription factor. It orchestrates cellular responses, particularly in the management of endoplasmic reticulum stress, amino acid deprivation, and oxidative challenges. ATF4's primary function lies in regulating gene expression to ensure cell survival during stressful conditions. However, when considering its involvement in ferroptosis, characterized by severe lipid peroxidation and pronounced endoplasmic reticulum stress, the ATF4 pathway can either inhibit or promote ferroptosis. This intricate relationship underscores the complexity of cellular responses to varying stress levels. Understanding the connections between ATF4, ferroptosis, and endoplasmic reticulum stress holds promise for innovative cancer therapies, especially in addressing apoptosis-resistant cells. In this review, we provide an overview of ATF4, including its structure, modifications, and functions, and delve into its dual role in both ferroptosis and cancer.
Similar content being viewed by others
Data availability
All data supporting the findings of this study are available within the paper.
References
Adomavicius T, Guaita M, Zhou Y et al (2019) The structural basis of translational control by eIF2 phosphorylation. Nat Commun 10(1):2136. https://doi.org/10.1038/s41467-019-10167-3
Ameri K, Harris AL (2008) Activating transcription factor 4. Int J Biochem Cell Biol 40(1):14–21
Ampofo E, Sokolowsky T, Götz C, Montenarh M (2013) Functional interaction of protein kinase CK2 and activating transcription factor 4 (ATF4), a key player in the cellular stress response. Biochim Biophys Acta 1833(3):439–451. https://doi.org/10.1016/j.bbamcr.2012.10.025
Andrysik Z, Sullivan KD, Kieft JS, Espinosa JM (2022) PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the integrated stress response. Nat Commun 13(1):7400. https://doi.org/10.1038/s41467-022-35089-5
Bagheri-Yarmand R, Sinha KM, Gururaj AE et al (2015) A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis. J Biol Chem 290(18):11749–11761. https://doi.org/10.1074/jbc.M114.619833
Baniulyte G, Durham SA, Merchant LE, Sammons MA (2023) Shared gene targets of the ATF4 and p53 transcriptional networks. Mol Cell Biol 43(8):426–449. https://doi.org/10.1080/10985549.2023.2229225
B’Chir W, Maurin A-C, Carraro V et al (2013) The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res 41(16):7683–7699. https://doi.org/10.1093/nar/gkt563
Bejjani F, Evanno E, Zibara K, Piechaczyk M, Jariel-Encontre I (2019) The AP-1 transcriptional complex: local switch or remote command? Biochim Biophys Acta Rev Cancer 1872(1):11–23. https://doi.org/10.1016/j.bbcan.2019.04.003
Berlanga JJ, Herrero S, de Haro C (1998) Characterization of the hemin-sensitive eukaryotic initiation factor 2alpha kinase from mouse nonerythroid cells. J Biol Chem 273(48):32340–32346
Cerezo M, Rocchi S (2017) New anti-cancer molecules targeting HSPA5/BIP to induce endoplasmic reticulum stress, autophagy and apoptosis. Autophagy 13(1):216–217. https://doi.org/10.1080/15548627.2016.1246107
Chen JJ, Throop MS, Gehrke L et al (1991) Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase. Proc Natl Acad Sci U S A 88(17):7729–7733
Chen H, Song R, Wang G et al (2015) OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation. Sci Rep 5:13241. https://doi.org/10.1038/srep13241
Chen M-S, Wang S-F, Hsu C-Y et al (2017) CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway. Oncotarget 8(70):114588–114602. https://doi.org/10.18632/oncotarget.23055
Chen Y, Mi Y, Zhang X et al (2019) Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells. J Exp Clin Cancer Res 38(1):402. https://doi.org/10.1186/s13046-019-1413-7
Chen X, Kang R, Kroemer G, Tang D (2021a) Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol 18(5):280–296. https://doi.org/10.1038/s41571-020-00462-0
Chen X, Kang R, Kroemer G, Tang D (2021b) Targeting ferroptosis in pancreatic cancer: a double-edged sword. Trends Cancer 7(10):891–901. https://doi.org/10.1016/j.trecan.2021.04.005
Chen X, Li J, Kang R, Klionsky DJ, Tang D (2021c) Ferroptosis: machinery and regulation. Autophagy 17(9):2054–2081. https://doi.org/10.1080/15548627.2020.1810918
Chen X, Huang J, Yu C et al (2022) A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nat Commun 13(1):6318. https://doi.org/10.1038/s41467-022-34096-w
Chen F, Cai X, Kang R, Liu J, Tang D (2023) Autophagy-dependent ferroptosis in cancer. Antioxid Redox Signal. https://doi.org/10.1089/ars.2022.0202
Cho I-J, Kim D, Kim E-O et al (2021) Cystine and methionine deficiency promotes ferroptosis by inducing B-cell translocation gene 1. Antioxidants (basel) 10(10):1543. https://doi.org/10.3390/antiox10101543
Chung J, Bauer DE, Ghamari A et al (2015) The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability. Sci Signal 8(372):ra34. https://doi.org/10.1126/scisignal.aaa5903
Cui J, Zhou Q, Yu M, Liu Y, Teng X, Gu X (2022) 4-tert-butylphenol triggers common carp hepatocytes ferroptosis via oxidative stress, iron overload, SLC7A11/GSH/GPX4 axis, and ATF4/HSPA5/GPX4 axis. Ecotoxicol Environ Saf 242:113944. https://doi.org/10.1016/j.ecoenv.2022.113944
Dai C, Chen X, Li J, Comish P, Kang R, Tang D (2020a) Transcription factors in ferroptotic cell death. Cancer Gene Ther 27(9):645–656. https://doi.org/10.1038/s41417-020-0170-2
Dai E, Han L, Liu J et al (2020b) Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun 11(1):6339. https://doi.org/10.1038/s41467-020-20154-8
Deng L, Mo M-Q, Zhong J, Li Z, Li G, Liang Y (2023) Iron overload induces islet β cell ferroptosis by activating ASK1/P-P38/CHOP signaling pathway. PeerJ 11:e15206. https://doi.org/10.7717/peerj.15206
Denton D, Kumar S (2019) Autophagy-dependent cell death. Cell Death Differ 26(4):605–616. https://doi.org/10.1038/s41418-018-0252-y
Dey S, Tameire F, Koumenis C (2013) PERK-ing up autophagy during MYC-induced tumorigenesis. Autophagy 9(4):612–614. https://doi.org/10.4161/auto.23486
Dey S, Sayers CM, Verginadis II et al (2015) ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J Clin Invest 125(7):2592–2608. https://doi.org/10.1172/JCI78031
Dierge E, Debock E, Guilbaud C et al (2021) Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab 33(8):1701–1715. https://doi.org/10.1016/j.cmet.2021.05.016
Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042
Dixon SJ, Patel DN, Welsch M et al (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3:e02523. https://doi.org/10.7554/eLife.02523
Drust DS, Troccoli NM, Jameson JL (1991) Binding specificity of cyclic adenosine 3′,5′-monophosphate-responsive element (CRE)-binding proteins and activating transcription factors to naturally occurring CRE sequence variants. Mol Endocrinol 5(10):1541–1551
Estes SD, Stoler DL, Anderson GR (1995) Normal fibroblasts induce the C/EBP beta and ATF-4 bZIP transcription factors in response to anoxia. Exp Cell Res 220(1):47–54
Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ (1999) Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J 339(Pt 1):135–141
Fessler E, Eckl E-M, Schmitt S et al (2020) A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579(7799):433–437. https://doi.org/10.1038/s41586-020-2076-4
Frank CL, Ge X, Xie Z, Zhou Y, Tsai L-H (2010) Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis. J Biol Chem 285(43):33324–33337. https://doi.org/10.1074/jbc.M110.140699
Galluzzi L, Vitale I, Warren S et al (2020) Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer 8(1):e0000337. https://doi.org/10.1136/jitc-2019-000337
Gao R, Kalathur RKR, Coto-Llerena M et al (2021) YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med 13(12):e14351. https://doi.org/10.15252/emmm.202114351
Gardner BM, Walter P (2011) Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 333(6051):1891–1894. https://doi.org/10.1126/science.1209126
Gouveia Roque C, Chung KM, McCurdy EP et al (2023) CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer’s disease gene expression linked to neuropathology. Sci Adv 9(9):eadd2671. https://doi.org/10.1126/sciadv.add2671
Guo H, Zhang J, Jiang Z et al (2023) Noncoding RNA circBtnl1 suppresses self-renewal of intestinal stem cells via disruption of Atf4 mRNA stability. EMBO J 42(6):e112039. https://doi.org/10.15252/embj.2022112039
Gwinn DM, Lee AG, Briones-Martin-Del-Campo M et al (2018) Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell 33(1):91. https://doi.org/10.1016/j.ccell.2017.12.003
Han L, Bai L, Fang X et al (2021a) SMG9 drives ferroptosis by directly inhibiting GPX4 degradation. Biochem Biophys Res Commun 567:92–98. https://doi.org/10.1016/j.bbrc.2021.06.038
Han S, Zhu L, Zhu Y et al (2021b) Targeting ATF4-dependent pro-survival autophagy to synergize glutaminolysis inhibition. Theranostics 11(17):8464–8479. https://doi.org/10.7150/thno.60028
Harding HP, Novoa I, Zhang Y et al (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6(5):1099–1108
Harding HP, Zhang Y, Zeng H et al (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11(3):619–633
He Z, Shen P, Feng L et al (2022) Cadmium induces liver dysfunction and ferroptosis through the endoplasmic stress-ferritinophagy axis. Ecotoxicol Environ Saf 245:114123. https://doi.org/10.1016/j.ecoenv.2022.114123
He F, Zhang P, Liu J et al (2023) ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis. J Hepatol 79(2):362–377. https://doi.org/10.1016/j.jhep.2023.03.016
Hiwatashi Y, Kanno K, Takasaki C et al (2011) PHD1 interacts with ATF4 and negatively regulates its transcriptional activity without prolyl hydroxylation. Exp Cell Res 317(20):2789–2799. https://doi.org/10.1016/j.yexcr.2011.09.005
Horiguchi M, Koyanagi S, Okamoto A, Suzuki SO, Matsunaga N, Ohdo S (2012) Stress-regulated transcription factor ATF4 promotes neoplastic transformation by suppressing expression of the INK4a/ARF cell senescence factors. Cancer Res 72(2):395–401. https://doi.org/10.1158/0008-5472.CAN-11-1891
Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E (2015) PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res 43:D512–D520. https://doi.org/10.1093/nar/gku1267
Hu X, Deng J, Yu T et al (2019) ATF4 deficiency promotes intestinal inflammation in mice by reducing uptake of glutamine and expression of antimicrobial peptides. Gastroenterology 156(4):1098–1111. https://doi.org/10.1053/j.gastro.2018.11.033
Huang C, Santofimia-Castaño P, Liu X et al (2021) NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner. Cell Death Discov 7(1):269. https://doi.org/10.1038/s41420-021-00662-2
Jin H-O, Seo S-K, Woo S-H et al (2009) Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4. IUBMB Life 61(12):1153–1158. https://doi.org/10.1002/iub.271
Kang L, Wang D, Shen T et al (2023) PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma. Cell Death Dis 14(3):193. https://doi.org/10.1038/s41419-023-05719-x
Kim W, Bennett EJ, Huttlin EL et al (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44(2):325–340. https://doi.org/10.1016/j.molcel.2011.08.025
Kim MG, Yang JH, Kim KM et al (2015) Regulation of Toll-like receptor-mediated Sestrin2 induction by AP-1, Nrf2, and the ubiquitin-proteasome system in macrophages. Toxicol Sci 144(2):425–435. https://doi.org/10.1093/toxsci/kfv012
Kim R, Hashimoto A, Markosyan N et al (2022a) Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612(7939):338–346. https://doi.org/10.1038/s41586-022-05443-0
Kim SW, Ahn B-Y, Tran TTV, Pyun J-H, Kang J-S, Leem Y-E (2022b) PRMT1 suppresses doxorubicin-induced cardiotoxicity by inhibiting endoplasmic reticulum stress. Cell Signal 98:110412. https://doi.org/10.1016/j.cellsig.2022.110412
Kim M, Hwang S, Kim B et al (2023) YAP governs cellular adaptation to perturbation of glutamine metabolism by regulating ATF4-mediated stress response. Oncogene. https://doi.org/10.1038/s41388-023-02811-6
Köditz J, Nesper J, Wottawa M et al (2007) Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 110(10):3610–3617
Kohli E, Causse S, Baverel V et al (2021) Endoplasmic reticulum chaperones in viral infection: therapeutic perspectives. Microbiol Mol Biol Rev 85(4):e0003521. https://doi.org/10.1128/MMBR.00035-21
Kress JKC, Jessen C, Hufnagel A et al (2023) The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2. Cell Rep 42(7):112724. https://doi.org/10.1016/j.celrep.2023.112724
Kuang F, Liu J, Xie Y, Tang D, Kang R (2021) MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells. Cell Chem Biol 28(6):765–775. https://doi.org/10.1016/j.chembiol.2021.01.006
Kumar A, Tikoo S, Maity S et al (2012) Mammalian proapoptotic factor ChaC1 and its homologues function as γ-glutamyl cyclotransferases acting specifically on glutathione. EMBO Rep 13(12):1095–1101. https://doi.org/10.1038/embor.2012.156
Lane DJR, Alves F, Ayton S, Bush AI (2023) Striking a NRF2: the rusty and rancid vulnerabilities toward ferroptosis in Alzheimer’s disease. Antioxid Redox Signal. https://doi.org/10.1089/ars.2023.0318
Lanlan T, Yan Y, Wenjun D et al (2023) TXNDC12 inhibits lipid peroxidation and ferroptosis. iScience 26(12):108393. https://doi.org/10.1016/j.isci.2023.108393
Lassot I, Ségéral E, Berlioz-Torrent C et al (2001) ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol 21(6):2192–2202
Lassot I, Estrabaud E, Emiliani S, Benkirane M, Benarous R, Margottin-Goguet F (2005) p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain. J Biol Chem 280(50):41537–41545
Lee C-H, Chiang C-F, Lin F-H et al (2022) PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle. Front Endocrinol (lausanne) 13:1053882. https://doi.org/10.3389/fendo.2022.1053882
Lei G, Zhuang L, Gan B (2022) Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer 22(7):381–396. https://doi.org/10.1038/s41568-022-00459-0
Li C, Liu J, Hou W, Kang R, Tang D (2021a) STING1 promotes ferroptosis through MFN1/2-dependent mitochondrial fusion. Front Cell Dev Biol 9:698679. https://doi.org/10.3389/fcell.2021.698679
Li J-Y, Ren C, Wang L-X et al (2021b) Sestrin2 protects dendrite cells against ferroptosis induced by sepsis. Cell Death Dis 12(9):834. https://doi.org/10.1038/s41419-021-04122-8
Li J, Kang R, Tang D (2021c) Monitoring autophagy-dependent ferroptosis. Methods Cell Biol 165:163–176. https://doi.org/10.1016/bs.mcb.2020.10.012
Li X, Zheng J, Chen S, Meng F-D, Ning J, Sun S-L (2021d) Oleandrin, a cardiac glycoside, induces immunogenic cell death via the PERK/elF2α/ATF4/CHOP pathway in breast cancer. Cell Death Dis 12(4):314. https://doi.org/10.1038/s41419-021-03605-y
Li Z, Huang Z, Zhang H et al (2021e) IRE1-mTOR-PERK axis coordinates autophagy and ER stress-apoptosis induced by P2X7-mediated Ca2+ influx in osteoarthritis. Front Cell Dev Biol 9:695041. https://doi.org/10.3389/fcell.2021.695041
Li J, Liu J, Zhou Z et al (2023) Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer. Sci Transl Med 15(720):eadg3049. https://doi.org/10.1126/scitranslmed.adg3049
Lin Z, Liu J, Kang R, Yang M, Tang D (2021) Lipid metabolism in ferroptosis. Adv Biol (weinh) 5(8):e2100396. https://doi.org/10.1002/adbi.202100396
Lin Z, Liu J, Long F et al (2022) The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis. Nat Commun 13(1):7965. https://doi.org/10.1038/s41467-022-35707-2
Liu J, Kang R, Tang D (2021a) Metabolic checkpoint of ferroptosis resistance. Mol Cell Oncol 8(3):1901558. https://doi.org/10.1080/23723556.2021.1901558
Liu J, Song X, Kuang F et al (2021b) NUPR1 is a critical repressor of ferroptosis. Nat Commun 12(1):647. https://doi.org/10.1038/s41467-021-20904-2
Liu J, Kang R, Tang D (2022) Signaling pathways and defense mechanisms of ferroptosis. FEBS J 289(22):7038–7050. https://doi.org/10.1111/febs.16059
Liu J, Liu Y, Wang Y et al (2023) TMEM164 is a new determinant of autophagy-dependent ferroptosis. Autophagy 19(3):945–956. https://doi.org/10.1080/15548627.2022.2111635
Longchamp A, Mirabella T, Arduini A et al (2018) Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H2S production. Cell 173(1):117. https://doi.org/10.1016/j.cell.2018.03.001
Ludwig MP, Galbraith MD, Eduthan NP et al (2023) Proteasome inhibition sensitizes liposarcoma to MDM2 inhibition with Nutlin-3 by activating the ATF4/CHOP stress response pathway. Cancer Res 83(15):2543–2556. https://doi.org/10.1158/0008-5472.CAN-22-3173
Luengo A, Gui DY, Vander Heiden MG (2017) Targeting metabolism for cancer therapy. Cell Chem Biol 24(9):1161–1180. https://doi.org/10.1016/j.chembiol.2017.08.028
Luo M, Wu L, Zhang K et al (2018) miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ 25(8):1457–1472. https://doi.org/10.1038/s41418-017-0053-8
Ma S, Tang T, Probst G et al (2022) Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer. Nat Commun 13(1):1061. https://doi.org/10.1038/s41467-022-28691-0
Mallo GV, Fiedler F, Calvo EL et al (1997) Cloning and expression of the rat p8 cDNA, a new gene activated in pancreas during the acute phase of pancreatitis, pancreatic development, and regeneration, and which promotes cellular growth. J Biol Chem 272(51):32360–32369
Marasco ONJM, Roussel MR, Thakor N (2022) Probabilistic models of uORF-mediated ATF4 translation control. Math Biosci 343:108762. https://doi.org/10.1016/j.mbs.2021.108762
Martins I, Wang Y, Michaud M et al (2014) Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ 21(1):79–91. https://doi.org/10.1038/cdd.2013.75
Masson N, Ratcliffe PJ (2014) Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways. Cancer Metab 2(1):3. https://doi.org/10.1186/2049-3002-2-3
McIntyre RL, Molenaars M, Schomakers BV et al (2023) Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4. Cell Rep 42(1):111928. https://doi.org/10.1016/j.celrep.2022.111928
Mielnicki LM, Pruitt SC (1991) Isolation and nucleotide sequence of a murine cDNA homologous to human activating transcription factor 4. Nucleic Acids Res 19(22):6332
Miess H, Dankworth B, Gouw AM et al (2018) The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene 37(40):5435–5450. https://doi.org/10.1038/s41388-018-0315-z
Motooka Y, Toyokuni S (2023) Ferroptosis as ultimate target of cancer therapy. Antioxid Redox Signal 39(1–3):206–223. https://doi.org/10.1089/ars.2022.0048
Mukherjee D, Chakraborty S, Bercz L et al (2023) Tomatidine targets ATF4-dependent signaling and induces ferroptosis to limit pancreatic cancer progression. iScience 26(8):107408. https://doi.org/10.1016/j.isci.2023.107408
Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ (2009) CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol 182(1):466–476
Novoa I, Zeng H, Harding HP, Ron D (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153(5):1011–1022
Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 24(6):1243–1255
Pathria G, Scott DA, Feng Y et al (2018) Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J. https://doi.org/10.15252/embj.201899735
Peng C, Li X, Ao F et al (2023) Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1. J Transl Med 21(1):218. https://doi.org/10.1186/s12967-023-04067-w
Podust LM, Krezel AM, Kim Y (2001) Crystal structure of the CCAAT box/enhancer-binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA. J Biol Chem 276(1):505–513
Qing G, Li B, Vu A et al (2012) ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22(5):631–644. https://doi.org/10.1016/j.ccr.2012.09.021
Rimokh R, Rouault JP, Wahbi K et al (1991) A chromosome 12 coding region is juxtaposed to the MYC protooncogene locus in a t(8;12)(q24;q22) translocation in a case of B-cell chronic lymphocytic leukemia. Genes Chromosom Cancer 3(1):24–36
Ryan DG, Yang M, Prag HA et al (2021) Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism. Elife. https://doi.org/10.7554/eLife.72593
Schoch S, Cibelli G, Magin A, Steinmüller L, Thiel G (2001) Modular structure of cAMP response element binding protein 2 (CREB2). Neurochem Int 38(7):601–608
Schwind L, Zimmer AD, Götz C, Montenarh M (2015) CK2 phosphorylation of C/EBPδ regulates its transcription factor activity. Int J Biochem Cell Biol 61:81–89. https://doi.org/10.1016/j.biocel.2015.02.004
Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 123(9):3664–3671. https://doi.org/10.1172/JCI67230
Shao Y, Xu Y, Di H et al (2023) The inhibition of ORMDL3 prevents Alzheimer’s disease through ferroptosis by PERK/ATF4/HSPA5 pathway. IET Nanobiotechnol 17(3):182–196. https://doi.org/10.1049/nbt2.12113
Singleton DC, Harris AL (2012) Targeting the ATF4 pathway in cancer therapy. Expert Opin Ther Targets 16(12):1189–1202. https://doi.org/10.1517/14728222.2012.728207
Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS (2002) ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J Biol Chem 277(27):24120–24127
Smith SG, Haynes KA, Hegde AN (2020) Degradation of transcriptional repressor ATF4 during long-term synaptic plasticity. Int J Mol Sci 21(22):8543. https://doi.org/10.3390/ijms21228543
Soda T, Frank C, Ishizuka K et al (2013) DISC1-ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1. Mol Psychiatry 18(8):898–908. https://doi.org/10.1038/mp.2013.38
Stockwell BR (2022) Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185(14):2401–2421. https://doi.org/10.1016/j.cell.2022.06.003
Stockwell BR, Friedmann Angeli JP, Bayir H et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171(2):273–285. https://doi.org/10.1016/j.cell.2017.09.021
Sun X, Niu X, Chen R et al (2016a) Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64(2):488–500. https://doi.org/10.1002/hep.28574
Sun X, Ou Z, Chen R et al (2016b) Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63(1):173–184. https://doi.org/10.1002/hep.28251
Sun Y, Zheng Y, Wang C, Liu Y (2018) Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death Dis 9(7):753. https://doi.org/10.1038/s41419-018-0794-4
Suragani RNVS, Zachariah RS, Velazquez JG et al (2012) Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood 119(22):5276–5284. https://doi.org/10.1182/blood-2011-10-388132
Swanda RV, Ji Q, Wu X et al (2023) Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response. Mol Cell 83(18):3347. https://doi.org/10.1016/j.molcel.2023.08.004
Szewczyk MM, Luciani GM, Vu V et al (2022) PRMT5 regulates ATF4 transcript splicing and oxidative stress response. Redox Biol 51:102282. https://doi.org/10.1016/j.redox.2022.102282
Tabata S, Kojima Y, Sakamoto T et al (2023) L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis. Oncogene 42(16):1294–1307. https://doi.org/10.1038/s41388-023-02632-7
Tameire F, Verginadis II, Leli NM et al (2019) ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat Cell Biol 21(7):889–899. https://doi.org/10.1038/s41556-019-0347-9
Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G (2019) The molecular machinery of regulated cell death. Cell Res 29(5):347–364. https://doi.org/10.1038/s41422-019-0164-5
Tang Q, Ren L, Liu J et al (2020) Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4-ATF3-CHOP axis. Cell Prolif 53(1):e12706. https://doi.org/10.1111/cpr.12706
Tang D, Chen X, Kang R, Kroemer G (2021) Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107–125. https://doi.org/10.1038/s41422-020-00441-1
Tang D, Kang R, Zeh HJ, Lotze MT (2023a) The multifunctional protein HMGB1: 50 years of discovery. Nat Rev Immunol. https://doi.org/10.1038/s41577-023-00894-6
Tang D, Kroemer G, Kang R (2023b) Ferroptosis in hepatocellular carcinoma: from bench to bedside. Hepatology. https://doi.org/10.1097/HEP.0000000000000390
Teske BF, Wek SA, Bunpo P et al (2011) The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Mol Biol Cell 22(22):4390–4405. https://doi.org/10.1091/mbc.E11-06-0510
Tsujimoto A, Nyunoya H, Morita T, Sato T, Shimotohno K (1991) Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I. J Virol 65(3):1420–1426
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. https://doi.org/10.1126/science.1160809
Varone E, Decio A, Chernorudskiy A et al (2021) The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions. Oncogene 40(9):1721–1736. https://doi.org/10.1038/s41388-021-01659-y
Vattem KM, Wek RC (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A 101(31):11269–11274
Wang M, Kaufman RJ (2014) The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer 14(9):581–597. https://doi.org/10.1038/nrc3800
Wang M, Kaufman RJ (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529(7586):326–335. https://doi.org/10.1038/nature17041
Wang Q, Mora-Jensen H, Weniger MA et al (2009) ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc Natl Acad Sci U S A 106(7):2200–2205. https://doi.org/10.1073/pnas.0807611106
Wang C, Li H, Meng Q et al (2014) ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression. J Cell Mol Med 18(1):80–90. https://doi.org/10.1111/jcmm.12166
Wang L-X, Zhu X-M, Luo Y-N et al (2020) Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein. Cell Death Dis 11(2):125. https://doi.org/10.1038/s41419-020-2324-4
Wang Q, Bin C, Xue Q et al (2021) GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis 12(5):426. https://doi.org/10.1038/s41419-021-03718-4
Wang Y, Chen D, Xie H et al (2022c) AUF1 protects against ferroptosis to alleviate sepsis-induced acute lung injury by regulating NRF2 and ATF3. Cell Mol Life Sci 79(5):228. https://doi.org/10.1007/s00018-022-04248-8
Wang L, Choi K, Su T et al (2022a) Multiphase coalescence mediates Hippo pathway activation. Cell. https://doi.org/10.1016/j.cell.2022.09.036
Wang X, Zhang G, Dasgupta S et al (2022b) ATF4 protects the heart from failure by antagonizing oxidative stress. Circ Res 131(1):91. https://doi.org/10.1161/CIRCRESAHA.122.321050
Wang Y, Ali M, Zhang Q et al (2023) ATF4 transcriptionally activates SHH to promote proliferation, invasion, and migration of gastric cancer cells. Cancers (basel) 15(5):1429. https://doi.org/10.3390/cancers15051429
Wei W, Li Y, Wang C et al (2022) Diterpenoid Vinigrol specifically activates ATF4/DDIT3-mediated PERK arm of unfolded protein response to drive non-apoptotic death of breast cancer cells. Pharmacol Res 182:106285. https://doi.org/10.1016/j.phrs.2022.106285
Wek SA, Zhu S, Wek RC (1995) The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol Cell Biol 15(8):4497–4506
Wen Y, Chen H, Zhang L et al (2021) Glycyrrhetinic acid induces oxidative/nitrative stress and drives ferroptosis through activating NADPH oxidases and iNOS, and depriving glutathione in triple-negative breast cancer cells. Free Radic Biol Med 173:41–51. https://doi.org/10.1016/j.freeradbiomed.2021.07.019
Wu J, Minikes AM, Gao M et al (2019) Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572(7769):402–406. https://doi.org/10.1038/s41586-019-1426-6
Wu S, Zhu C, Tang D, Dou QP, Shen J, Chen X (2021) The role of ferroptosis in lung cancer. Biomark Res 9(1):82. https://doi.org/10.1186/s40364-021-00338-0
Xiao Z, Dai Z, Locasale JW (2019) Metabolic landscape of the tumor microenvironment at single cell resolution. Nat Commun 10(1):3763. https://doi.org/10.1038/s41467-019-11738-0
Xiao W, Sun Y, Xu J, Zhang N, Dong L (2022) uORF-mediated translational regulation of ATF4 serves as an evolutionarily conserved mechanism contributing to non-small-cell lung cancer (NSCLC) and stress response. J Mol Evol 90(5):375–388. https://doi.org/10.1007/s00239-022-10068-y
Xie Y, Hou W, Song X et al (2016) Ferroptosis: process and function. Cell Death Differ 23(3):369–379. https://doi.org/10.1038/cdd.2015.158
Xie Y, Hou T, Liu J et al (2023a) Autophagy-dependent ferroptosis as a potential treatment for glioblastoma. Front Oncol 13:1091118. https://doi.org/10.3389/fonc.2023.1091118
Xie Y, Kang R, Klionsky DJ, Tang D (2023b) GPX4 in cell death, autophagy, and disease. Autophagy 19:1–18. https://doi.org/10.1080/15548627.2023.2218764
Xue Q, Yan D, Chen X et al (2023a) Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy 19:1–15. https://doi.org/10.1080/15548627.2023.2165323
Xue Y, Lu F, Chang Z et al (2023b) Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade. Nat Commun 14(1):4758. https://doi.org/10.1038/s41467-023-40518-0
Yang X, Matsuda K, Bialek P et al (2004) ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell 117(3):387–398
Yang WS, SriRamaratnam R, Welsch ME et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156(1–2):317–331. https://doi.org/10.1016/j.cell.2013.12.010
Yang W-H, Ding C-KC, Sun T et al (2019) The Hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep 28(10):2501. https://doi.org/10.1016/j.celrep.2019.07.107
Yilmaz M, Christofori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28(1–2):15–33. https://doi.org/10.1007/s10555-008-9169-0
Yin Z, Machius M, Nestler EJ, Rudenko G (2017) Activator protein-1: redox switch controlling structure and DNA-binding. Nucleic Acids Res 45(19):11425–11436. https://doi.org/10.1093/nar/gkx795
Yu F, Wei J, Cui X et al (2021) Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response. Nucleic Acids Res 49(10):5779–5797. https://doi.org/10.1093/nar/gkab415
Yuniati L, van der Meer LT, Tijchon E et al (2016) Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress. Oncotarget 7(3):3128–3143. https://doi.org/10.18632/oncotarget.6519
Zeng T, Zhou Y, Yu Y et al (2023) rmMANF prevents sepsis-associated lung injury via inhibiting endoplasmic reticulum stress-induced ferroptosis in mice. Int Immunopharmacol 114:109608. https://doi.org/10.1016/j.intimp.2022.109608
Zhang R, Kang R, Tang D (2023) Ferroptosis in gastrointestinal cancer: from mechanisms to implications. Cancer Lett 561:216147. https://doi.org/10.1016/j.canlet.2023.216147
Zhao C, Yu D, He Z et al (2021) Endoplasmic reticulum stress-mediated autophagy activation is involved in cadmium-induced ferroptosis of renal tubular epithelial cells. Free Radic Biol Med 175:236–248. https://doi.org/10.1016/j.freeradbiomed.2021.09.008
Zhu S, Zhang Q, Sun X et al (2017) HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res 77(8):2064–2077. https://doi.org/10.1158/0008-5472.CAN-16-1979
Zhu H-L, Shi X-T, Xu X-F et al (2021) Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts. Redox Biol 40:101854. https://doi.org/10.1016/j.redox.2021.101854
Zhu W, Li Y, Li M et al (2023) Bioinformatics analysis of molecular interactions between endoplasmic reticulum stress and ferroptosis under stress exposure. Anal Cell Pathol (amst) 2023:9979291. https://doi.org/10.1155/2023/9979291
Zielke S, Kardo S, Zein L et al (2021) ATF4 links ER stress with reticulophagy in glioblastoma cells. Autophagy 17(9):2432–2448. https://doi.org/10.1080/15548627.2020.1827780
Zou Y, Palte MJ, Deik AA et al (2019) A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun 10(1):1617. https://doi.org/10.1038/s41467-019-09277-9
Zyryanova AF, Kashiwagi K, Rato C et al (2021) ISRIB blunts the integrated stress response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B. Mol Cell 81(1):88. https://doi.org/10.1016/j.molcel.2020.10.031
Funding
Research by J.L. was supported by grants from the National Natural Sciences Foundation of China (82070613).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Tang, H., Kang, R., Liu, J. et al. ATF4 in cellular stress, ferroptosis, and cancer. Arch Toxicol 98, 1025–1041 (2024). https://doi.org/10.1007/s00204-024-03681-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-024-03681-x