{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T16:46:27Z","timestamp":1789404387356,"version":"build-2803163510"},"reference-count":96,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Econom\u00eda y Competitividad","award":["SAF2015-64383-P"],"award-info":[{"award-number":["SAF2015-64383-P"]}]},{"name":"Ministerio de Econom\u00eda y Competitividad","award":["PGC2018-093960-B-I00"],"award-info":[{"award-number":["PGC2018-093960-B-I00"]}]},{"name":"Ministerio de Econom\u00eda y Competitividad","award":["PY20-00754"],"award-info":[{"award-number":["PY20-00754"]}]},{"name":"Ministerio de Econom\u00eda y Competitividad","award":["CB16\/12\/00421"],"award-info":[{"award-number":["CB16\/12\/00421"]}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["SAF2015-64383-P"],"award-info":[{"award-number":["SAF2015-64383-P"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PGC2018-093960-B-I00"],"award-info":[{"award-number":["PGC2018-093960-B-I00"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PY20-00754"],"award-info":[{"award-number":["PY20-00754"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["CB16\/12\/00421"],"award-info":[{"award-number":["CB16\/12\/00421"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Junta de Andaluc\u00eda","award":["SAF2015-64383-P"],"award-info":[{"award-number":["SAF2015-64383-P"]}]},{"name":"Junta de Andaluc\u00eda","award":["PGC2018-093960-B-I00"],"award-info":[{"award-number":["PGC2018-093960-B-I00"]}]},{"name":"Junta de Andaluc\u00eda","award":["PY20-00754"],"award-info":[{"award-number":["PY20-00754"]}]},{"name":"Junta de Andaluc\u00eda","award":["CB16\/12\/00421"],"award-info":[{"award-number":["CB16\/12\/00421"]}]},{"name":"CIBERONC ISCIII","award":["SAF2015-64383-P"],"award-info":[{"award-number":["SAF2015-64383-P"]}]},{"name":"CIBERONC ISCIII","award":["PGC2018-093960-B-I00"],"award-info":[{"award-number":["PGC2018-093960-B-I00"]}]},{"name":"CIBERONC ISCIII","award":["PY20-00754"],"award-info":[{"award-number":["PY20-00754"]}]},{"name":"CIBERONC ISCIII","award":["CB16\/12\/00421"],"award-info":[{"award-number":["CB16\/12\/00421"]}]},{"name":"European Community","award":["SAF2015-64383-P"],"award-info":[{"award-number":["SAF2015-64383-P"]}]},{"name":"European Community","award":["PGC2018-093960-B-I00"],"award-info":[{"award-number":["PGC2018-093960-B-I00"]}]},{"name":"European Community","award":["PY20-00754"],"award-info":[{"award-number":["PY20-00754"]}]},{"name":"European Community","award":["CB16\/12\/00421"],"award-info":[{"award-number":["CB16\/12\/00421"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a response to ER stress, both normal and tumor cells launch a set of signaling pathways known as the unfolded protein response (UPR) to restore ER proteostasis and maintain cell viability and function. However, under sustained ER stress, an apoptotic cell death process can be induced and this has been the subject of different review articles, although the role of the TRAIL-R2\/DR5-activated extrinsic pathway of apoptosis has not yet been thoroughly summarized. In this Review, we provide an updated overview of the molecular mechanisms regulating cell fate decisions in tumor cells undergoing ER stress and discuss the role of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2\/DR5) in the final outcome of UPR signaling. Particularly, we focus on the mechanisms controlling cellular FLICE-like inhibitory protein (FLIP) levels in tumor cells undergoing ER stress, which may represent a potential target for therapeutic intervention in cancer.<\/jats:p>","DOI":"10.3390\/ijms23168987","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T01:47:21Z","timestamp":1660528041000},"page":"8987","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Restoring TRAILR2\/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer"],"prefix":"10.3390","volume":"23","author":[{"given":"Roc\u00edo","family":"Mora-Molina","sequence":"first","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Avda Am\u00e9rico Vespucio 24, 41092 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9351-9690","authenticated-orcid":false,"given":"Abelardo","family":"L\u00f3pez-Rivas","sequence":"additional","affiliation":[{"name":"Centro Andaluz de Biolog\u00eda Molecular y Medicina Regenerativa-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Avda Am\u00e9rico Vespucio 24, 41092 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/B978-0-12-407704-1.00005-1","article-title":"Endoplasmic Reticulum and the Unfolded Protein Response. Dynamics and Metabolic Integration","volume":"301","author":"Bravo","year":"2013","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/nature17041","article-title":"Protein Misfolding in the Endoplasmic Reticulum as a Conduit to Human Disease","volume":"529","author":"Wang","year":"2016","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a033928","DOI":"10.1101\/cshperspect.a033928","article-title":"Chaperoning Endoplasmic Reticulum\u2013Associated Degradation (ERAD) and Protein Conformational Diseases","volume":"11","author":"Needham","year":"2019","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ceb.2018.04.004","article-title":"Mechanistic Insights into ER-Associated Protein Degradation","volume":"53","author":"Wu","year":"2018","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The Unfolded Protein Response and Cell Fate Control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","article-title":"Mechanisms, Regulation and Functions of the Unfolded Protein Response","volume":"21","author":"Hetz","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.devcel.2007.07.005","article-title":"ATF6\u03b1 Optimizes Long-Term Endoplasmic Reticulum Function to Protect Cells from Chronic Stress","volume":"13","author":"Wu","year":"2007","journal-title":"Dev. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1083\/jcb.200406136","article-title":"XBP1: A Link between the Unfolded Protein Response, Lipid Biosynthesis, and Biogenesis of the Endoplasmic Reticulum","volume":"167","author":"Sriburi","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.molcel.2007.06.011","article-title":"XBP1 Controls Diverse Cell Type- and Condition-Specific Transcriptional Regulatory Networks","volume":"27","author":"Zhou","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7683","DOI":"10.1093\/nar\/gkt563","article-title":"The EIF2\u03b1\/ATF4 Pathway is Essential for Stress-Induced Autophagy Gene Expression","volume":"41","author":"Maurin","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/35014014","article-title":"Dynamic Interaction of BiP and ER Stress Transducers in the Unfolded-Protein Response","volume":"2","author":"Bertolotti","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e30700","DOI":"10.7554\/eLife.30700","article-title":"An Unfolded Protein-Induced Conformational Switch Activates Mammalian IRE1","volume":"6","author":"Nguyen","year":"2017","journal-title":"eLife"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1074\/jbc.RA117.001294","article-title":"The Luminal Domain of the ER Stress Sensor Protein PERK Binds Misfolded Proteins and Thereby Triggers PERK Oligomerization","volume":"293","author":"Wang","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/0092-8674(93)90648-A","article-title":"Transcriptional Induction of Genes Encoding Endoplasmic Reticulum Resident Proteins Requires a Transmembrane Protein Kinase","volume":"73","author":"Cox","year":"1993","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nrc3800","article-title":"The Impact of the Endoplasmic Reticulum Protein-Folding Environment on Cancer Development","volume":"14","author":"Wang","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0092-8674(01)00611-0","article-title":"XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor","volume":"107","author":"Yoshida","year":"2001","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/415092a","article-title":"IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA","volume":"415","author":"Calfon","year":"2002","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7024","DOI":"10.1074\/jbc.M609490200","article-title":"Coordinate Regulation of Phospholipid Biosynthesis and Secretory Pathway Gene Expression in XBP-1(S)-Induced Endoplasmic Reticulum Biogenesis","volume":"282","author":"Sriburi","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.2337\/db16-0052","article-title":"Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing through Modulating MicroRNAs","volume":"66","author":"Wang","year":"2017","journal-title":"Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1126\/science.1129631","article-title":"Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response","volume":"313","author":"Hollien","year":"2006","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1126\/science.1226191","article-title":"IRE1a Cleaves Select MicroRNAs During ER Stress to Derepress Translation of Proapoptotic Caspase-2","volume":"338","author":"Upton","year":"2012","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.celrep.2014.09.016","article-title":"Ire1 Has Distinct Catalytic Mechanisms for XBP1\/HAC1 Splicing and RIDD","volume":"9","author":"Tam","year":"2014","journal-title":"Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/16729","article-title":"Protein Translation and Folding Are Coupled by an Endoplasmic-Reticulum-Resident Kinase","volume":"397","author":"Harding","year":"1999","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1083\/jcb.200408003","article-title":"Translation Reinitiation at Alternative Open Reading Frames Regulates Gene Expression in an Integrated Stress Response","volume":"167","author":"Lu","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11269","DOI":"10.1073\/pnas.0400541101","article-title":"Reinitiation Involving Upstream ORFs Regulates ATF4 MRNA Translation in Mammalian Cells","volume":"10","author":"Vattem","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S1097-2765(03)00105-9","article-title":"An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress","volume":"11","author":"Harding","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","article-title":"Regulated Translation Initiation Controls Stress-Induced Gene Expression in Mammalian Cells","volume":"6","author":"Harding","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1042\/bj3390135","article-title":"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","volume":"339","author":"Fawcett","year":"1999","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ncb2738","article-title":"ER-Stress-Induced Transcriptional Regulation Increases Protein Synthesis Leading to Cell Death","volume":"15","author":"Han","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1101\/gad.1250704","article-title":"CHOP Induces Death by Promoting Protein Synthesis and Oxidation in the Stressed Endoplasmic Reticulum","volume":"18","author":"Marciniak","year":"2004","journal-title":"Genes Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34864","DOI":"10.1074\/jbc.M301107200","article-title":"Delineation of a Negative Feedback Regulatory Loop That Controls Protein Translation during Endoplasmic Reticulum Stress","volume":"278","author":"Ma","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.cell.2007.04.027","article-title":"ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim","volume":"129","author":"Puthalakath","year":"2007","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"45495","DOI":"10.1074\/jbc.M406933200","article-title":"CHOP is Involved in Endoplasmic Reticulum Stress-Induced Apoptosis by Enhancing DR5 Expression in Human Carcinoma Cells","volume":"279","author":"Yamaguchi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"16938","DOI":"10.1523\/JNEUROSCI.1598-10.2010","article-title":"Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress is Regulated by ATF4-CHOP-Mediated Induction of the Bcl-2 Homology 3-Only Member PUMA","volume":"30","author":"Galehdar","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/sj.emboj.7600596","article-title":"TRB3, a Novel ER Stress-Inducible Gene, is Induced via ATF4-CHOP Pathway and is Involved in Cell Death","volume":"24","author":"Ohoka","year":"2005","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1128\/MCB.21.4.1249-1259.2001","article-title":"Gadd153 Sensitizes Cells to Endoplasmic Reticulum Stress by Down-Regulating Bcl2 and Perturbing the Cellular Redox State","volume":"21","author":"McCullough","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3787","DOI":"10.1091\/mbc.10.11.3787","article-title":"Mammalian Transcription Factor ATF6 is Synthesized as a Transmembrane Protein and Activated by Proteolysis in Response to Endoplasmic Reticulum Stress","volume":"10","author":"Haze","year":"1999","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17775","DOI":"10.1073\/pnas.0910342106","article-title":"In Vitro Reconstitution of ER-Stress Induced ATF6 Transport in COPII Vesicles","volume":"106","author":"Schindler","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/S1097-2765(00)00133-7","article-title":"ER Stress Induces Cleavage of Membrane-Bound ATF6 by the Same Proteases That Process SREBPs","volume":"6","author":"Ye","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41568-020-00312-2","article-title":"Endoplasmic Reticulum Stress Signals in the Tumour and Its Microenvironment","volume":"21","author":"Chen","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.tibs.2011.03.001","article-title":"Modulating Stress Responses by the UPRosome: A Matter of Life and Death","volume":"36","author":"Woehlbier","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/s41419-017-0164-7","article-title":"Involvement of Both Caspase-8 and Noxa-Activated Pathways in Endoplasmic Reticulum Stress-Induced Apoptosis in Triple-Negative Breast Tumor Cells Article","volume":"9","author":"Gil","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1158\/0008-5472.CAN-13-1747","article-title":"Activated ERBB2\/HER2 Licenses Sensitivity to Apoptosis upon Endoplasmic Reticulum Stress through a PERK-Dependent Pathway","volume":"74","author":"Palacios","year":"2014","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.bbamcr.2010.11.012","article-title":"Integrating Stress Signals at the Endoplasmic Reticulum: The BCL-2 Protein Family Rheostat","volume":"1813","author":"Rodriguez","year":"2011","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1083\/jcb.200302084","article-title":"Bax and Bak Can Localize to the Endoplasmic Reticulum to Initiate Apoptosis","volume":"162","author":"Zong","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"jcs218107","DOI":"10.1242\/jcs.218107","article-title":"The UPRosome\u2014Decoding Novel Biological Outputs of IRE1\u03b1 Function","volume":"133","author":"Urra","year":"2020","journal-title":"J. Cell Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1126\/science.287.5453.664","article-title":"Coupling of Stress in the ER to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1","volume":"287","author":"Urano","year":"2000","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/sj.embor.7400687","article-title":"Tumour Necrosis Factor Receptor 1 Mediates Endoplasmic Reticulum Stress-Induced Activation of the MAP Kinase JNK","volume":"7","author":"Yang","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1128\/MCB.26.8.3071-3084.2006","article-title":"Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1\u03b1-Mediated NF-\u039aB Activation and Down-Regulation of TRAF2 Expression","volume":"26","author":"Hu","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e555","DOI":"10.1038\/cddis.2014.523","article-title":"RIPK1 Promotes Death Receptor-Independent Caspase-8-Mediated Apoptosis under Unresolved ER Stress Conditions","volume":"5","author":"Estornes","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.1123480","article-title":"Proapoptotic BAX and BAK Modulate the Unfolded Protein Response by a Direct Interaction with IRE1\u03b1","volume":"312","author":"Hetz","year":"2006","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1038\/emboj.2012.84","article-title":"BH3-Only Proteins Are Part of a Regulatory Network That Control the Sustained Signalling of the Unfolded Protein Response Sensor IRE1\u03b1","volume":"31","author":"Rodriguez","year":"2012","journal-title":"EMBO J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1128\/MCB.00013-08","article-title":"Caspase-2 Cleavage of BID is a Critical Apoptotic Signal Downstream of Endoplasmic Reticulum Stress","volume":"28","author":"Upton","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.cmet.2012.07.007","article-title":"IRE1\u03b1 Induces Thioredoxin-Interacting Protein to Activate the NLRP3 Inflammasome and Promote Programmed Cell Death under Irremediable ER Stress","volume":"16","author":"Lerner","year":"2012","journal-title":"Cell Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1016\/j.bbamcr.2013.07.024","article-title":"When ER Stress Reaches a Dead End","volume":"1833","author":"Urra","year":"2013","journal-title":"Biochim. Biophys. Acta-Mol. Cell Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.molcel.2018.06.038","article-title":"Coordination between Two Branches of the Unfolded Protein Response Determines Apoptotic Cell Fate","volume":"71","author":"Chang","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1254312","article-title":"Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis","volume":"345","author":"Lu","year":"2014","journal-title":"Science"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6755","DOI":"10.1128\/MCB.20.18.6755-6767.2000","article-title":"ATF6 Activated by Proteolysis Binds in the Presence of NF-Y (CBF) Directly to the cis-Acting Element Responsible for the Mammalian Unfolded Protein Response","volume":"20","author":"Yoshida","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"35227","DOI":"10.1074\/jbc.M111.233502","article-title":"Activating Transcription Factor-6 (ATF6) Mediates Apoptosis with Reduction of Myeloid Cell Leukemia Sequence 1 (Mcl-1) Protein via Induction of WW Domain Binding Protein","volume":"286","author":"Morishima","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e52291","DOI":"10.7554\/eLife.52291","article-title":"Misfolded Proteins Bind and Activate Death Receptor 5 to Trigger Apoptosis during Unresolved Endoplasmic Reticulum Stress","volume":"9","author":"Lam","year":"2020","journal-title":"eLife"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e00479-16","DOI":"10.1128\/MCB.00479-16","article-title":"Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors","volume":"37","author":"Iurlaro","year":"2017","journal-title":"Mol. Cell. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"93688","DOI":"10.18632\/oncotarget.21458","article-title":"Oncogenic P95HER2\/611CTF Primes Human Breast Epithelial Cells for Metabolic Stress-Induced down-Regulation of FLIP and Activation of TRAIL-R\/Caspase-8-Dependent Apoptosis","volume":"8","author":"Yerbes","year":"2017","journal-title":"Oncotarget"},{"key":"ref_63","first-page":"3883","article-title":"C-FLIP Gene Silencing Eliminates Tumor Cells in Breast Cancer Xenografts without Affecting Stromal Cells","volume":"29","author":"Day","year":"2009","journal-title":"Anticancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.molcel.2016.02.023","article-title":"Co-Operative and Hierarchical Binding of c-FLIP and Caspase-8: A Unified Model Defines How c-FLIP Isoforms Differentially Control Cell Fate","volume":"61","author":"Hughes","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e49254","DOI":"10.15252\/embr.201949254","article-title":"A Revised Model of TRAIL -R2 DISC Assembly Explains How FLIP (L) Can Inhibit or Promote Apoptosis","volume":"21","author":"Humphreys","year":"2020","journal-title":"EMBO Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8858","DOI":"10.1158\/0008-5472.CAN-06-0808","article-title":"Flavopiridol Induces Cellular FLICE-Inhibitory Protein Degradation by the Proteasome and Promotes TRAIL-Induced Early Signaling and Apoptosis in Breast Tumor Cells","volume":"66","author":"Palacios","year":"2006","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5754","DOI":"10.1158\/0008-5472.CAN-06-3585","article-title":"C-FLIP: A Key Regulator of Colorectal Cancer Cell Death","volume":"67","author":"Wilson","year":"2007","journal-title":"Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/cdd.2014.197","article-title":"The Endogenous Caspase-8 Inhibitor c-FLIPL Regulates ER Morphology and Crosstalk with Mitochondria","volume":"22","author":"Marini","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41419-022-04574-6","article-title":"CFLIP Downregulation is an Early Event Required for Endoplasmic Reticulum Stress-Induced Apoptosis in Tumor Cells","volume":"13","author":"Rehm","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"7993","DOI":"10.2147\/IJN.S146927","article-title":"Drug Delivery to Solid Tumors: The Predictive Value of the Multicellular Tumor Spheroid Model for Nanomedicine Screening","volume":"12","author":"Millard","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.pharmthera.2016.03.013","article-title":"Three-Dimensional Culture Systems in Cancer Research: Focus on Tumor Spheroid Model","volume":"163","author":"Nath","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"30321","DOI":"10.3390\/ijms161226232","article-title":"FLIP the Switch: Regulation of Apoptosis and Necroptosis by CFLIP","volume":"16","author":"Tsuchiya","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_73","first-page":"203","article-title":"Comparison of Cancer Cells in 2D vs 3D Culture Reveals Differences in AKT-MTOR-S6K Signaling and Drug Responses","volume":"130","author":"Riedl","year":"2017","journal-title":"J. Cell Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10549-009-0502-2","article-title":"HER2 Signaling Pathway Activation and Response of Breast Cancer Cells to HER2-Targeting Agents is Dependent Strongly on the 3D Microenvironment","volume":"122","author":"Weigelt","year":"2010","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5205","DOI":"10.4049\/jimmunol.162.9.5205","article-title":"Cell Cycle-Dependent Regulation of FLIP Levels and Susceptibility to Fas-Mediated Apoptosis","volume":"162","author":"Griffith","year":"1999","journal-title":"J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5225","DOI":"10.1038\/sj.onc.1204673","article-title":"Accelerated Degradation of Cellular FLIP Protein through the Ubiquitin-Proteasome Pathway in P53-Mediated Apoptosis of Human Cancer Cells","volume":"20","author":"Fukazawa","year":"2001","journal-title":"Oncogene"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"14513","DOI":"10.1074\/jbc.M807918200","article-title":"Activation-Induced Degradation of FLIPL is Mediated via the Phosphatidylinositol 3-Kinase\/Akt Signaling Pathway in Macrophages","volume":"284","author":"Shi","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"12777","DOI":"10.1074\/jbc.M112.431320","article-title":"Novel Phosphorylation and Ubiquitination Sites Regulate Reactive Oxygen Species-Dependent Degradation of Anti-Apoptotic c-FLIP Protein","volume":"288","author":"Matsuzawa","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7043","DOI":"10.1074\/jbc.M211278200","article-title":"Calcium\/Calmodulin-Dependent Protein Kinase II Regulation of c-FLIP Expression and Phosphorylation in Modulation of Fas-Mediated Signaling in Malignant Glioma Cells","volume":"278","author":"Yang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"42044","DOI":"10.1074\/jbc.M510080200","article-title":"Nitric Oxide Negatively Regulates Fas CD95-Induced Apoptosis through Inhibition of Ubiquitin-Proteasome-Mediated Degradation of FLICE Inhibitory Protein","volume":"280","author":"Chanvorachote","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.cell.2006.01.021","article-title":"The E3 Ubiquitin Ligase Itch Couples JNK Activation to TNF\u03b1-Induced Cell Death by Inducing c-FLIPL Turnover","volume":"124","author":"Chang","year":"2006","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1016\/j.febslet.2012.07.067","article-title":"Cbl-b-Dependent Degradation of FLIPL is Involved in ATO-Induced Autophagy in Leukemic K562 and Gastric Cancer Cells","volume":"586","author":"Zhang","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1158\/0008-5472.CAN-08-0673","article-title":"Cisplatin Induces P53-Dependent FLICE-like Inhibitory Protein Ubiquitination in Ovarian Cancer Cells","volume":"68","author":"Abedini","year":"2008","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1074\/jbc.M803533200","article-title":"Down-Regulation of the de-Ubiquitinating Enzyme Ubiquitin-Specific Protease 2 Contributes to Tumor Necrosis Factor-\u03b1-Induced Hepatocyte Survival","volume":"284","author":"Haimerl","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/onc.2013.52","article-title":"ATM Kinase Activity Modulates ITCH E3-Ubiquitin Ligase Activity","volume":"33","author":"Santini","year":"2014","journal-title":"Oncogene"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3814","DOI":"10.3748\/wjg.v26.i26.3814","article-title":"Expression of Notch Pathway Components (Numb, Itch, and Siah-1) in Colorectal Tumors: A Clinicopathological Study","volume":"26","author":"Gonulcu","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41419-017-0165-6","article-title":"C-FLIP is a Target of the E3 Ligase Deltex1 in Gastric Cancer","volume":"9","author":"Hsu","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6053","DOI":"10.1074\/jbc.M111.300137","article-title":"Tumor Necrosis Factor (TNF) Receptor-Associated Factor 7 is Required for TNF\u03b1-Induced Jun NH2-Terminal Kinase Activation and Promotes Cell Death by Regulating Polyubiquitination and Lysosomal Degradation of c-FLIP Protein","volume":"287","author":"Scudiero","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"20062","DOI":"10.1074\/jbc.RA118.005449","article-title":"Linear Ubiquitination of CFLIP Induced by LUBAC Contributes to TNF-Induced Apoptosis","volume":"293","author":"Tang","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1475-2867-12-54","article-title":"Down-Regulation of Cellular FLICE-Inhibitory Protein (Long Form) Contributes to Apoptosis Induced by Hsp90 Inhibition in Human Lung Cancer Cells","volume":"12","author":"Wang","year":"2012","journal-title":"Cancer Cell Int."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1038\/s41418-020-0539-7","article-title":"The SCFSkp2 Ubiquitin Ligase Complex Modulates TRAIL-R2-Induced Apoptosis by Regulating FLIP(L)","volume":"27","author":"Roberts","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/cdd.2012.8","article-title":"Identification of an Acetylation-Dependant Ku70\/FLIP Complex That Regulates FLIP Expression and HDAC Inhibitor-Induced Apoptosis","volume":"19","author":"Kerr","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1158\/1078-0432.CCR-10-0052","article-title":"Prognostic Significance of TRAIL Signaling Molecules in Stage II and III Colorectal Cancer","volume":"16","author":"McLornan","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/path.835","article-title":"Increased Expression of CFLIPL in Colonic Adenocarcinoma","volume":"194","author":"Ryu","year":"2001","journal-title":"J. Pathol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.3390\/cancers3021639","article-title":"Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy","volume":"3","author":"Safa","year":"2011","journal-title":"Cancers"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.1158\/1078-0432.CCR-06-2547","article-title":"Overexpression of FLIPL is an Independent Marker of Poor Prognosis in Colorectal Cancer Patients","volume":"13","author":"Ullenhag","year":"2007","journal-title":"Clin. Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/8987\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:07:35Z","timestamp":1760141255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/8987"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,12]]},"references-count":96,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23168987"],"URL":"https:\/\/doi.org\/10.3390\/ijms23168987","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,12]]}}}