{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:11:07Z","timestamp":1790482267069,"version":"4.1.0"},"reference-count":124,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,5,30]],"date-time":"2019-05-30T00:00:00Z","timestamp":1559174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"publisher","award":["Comit\u00e9 du Nord"],"award-info":[{"award-number":["Comit\u00e9 du Nord"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"publisher","award":["Comit\u00e9 de la Somme"],"award-info":[{"award-number":["Comit\u00e9 de la Somme"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Head and neck squamous cell carcinomas (HNSCC) encompass a heterogeneous group of solid tumors that arise from the upper aerodigestive tract. The tumor cells face multiple challenges including an acute demand of protein synthesis often driven by oncogene activation, limited nutrient and oxygen supply and exposure to chemo\/radiotherapy, which forces them to develop adaptive mechanisms such as the Unfolded Protein Response (UPR). It is now well documented that the UPR, a homeostatic mechanism, is induced at different stages of cancer progression in response to intrinsic (oncogenic activation) or extrinsic (microenvironment) perturbations. This review will discuss the role of the UPR in HNSCC as well as in the key processes that characterize the physiology of HNSCC. The role of the UPR in the clinical context of HNSCC will also be addressed.<\/jats:p>","DOI":"10.3390\/ijms20112654","type":"journal-article","created":{"date-parts":[[2019,5,30]],"date-time":"2019-05-30T11:07:44Z","timestamp":1559214464000},"page":"2654","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Impact and Relevance of the Unfolded Protein Response in HNSCC"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5178-0076","authenticated-orcid":false,"given":"Olivier","family":"Pluquet","sequence":"first","affiliation":[{"name":"Institut Pasteur de Lille, Universit\u00e9 de Lille, CNRS, UMR8161\u2013M3T\u2013Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5836-4646","authenticated-orcid":false,"given":"Antoine","family":"Galmiche","sequence":"additional","affiliation":[{"name":"Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Sud, 80054 Amiens, France"},{"name":"EA7516, Universit\u00e9 de Picardie Jules Verne (UPJV), 80054 Amiens, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1016\/S0140-6736(08)60728-X","article-title":"Head and neck cancer","volume":"371","author":"Argiris","year":"2008","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1002\/ijc.28112","article-title":"Head and neck cancer: From anatomy to biology","volume":"133","author":"Bose","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"761","DOI":"10.6004\/jnccn.2017.0101","article-title":"NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017","volume":"15","author":"Adelstein","year":"2017","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrc.2018.11","article-title":"The molecular landscape of head and neck cancer","volume":"18","author":"Leemans","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"(2015). Cancer Genome Atlas Network Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 517, 576\u2013582.","DOI":"10.1038\/nature14129"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.ccell.2016.04.004","article-title":"Squamous Cell Cancers: A Unified Perspective on Biology and Genetics","volume":"29","author":"Dotto","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.critrevonc.2018.05.003","article-title":"The unfolded protein response as a target for anticancer therapeutics","volume":"127","author":"Wang","year":"2018","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/boc.201800050","article-title":"The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance","volume":"111","author":"Madden","year":"2019","journal-title":"Biol. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.semcancer.2015.04.008","article-title":"Theme Series\u2014UPR in cancer","volume":"33","author":"Hetz","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e373","DOI":"10.1038\/oncsis.2017.72","article-title":"Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers","volume":"6","author":"Avril","year":"2017","journal-title":"Oncogenesis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1101\/gad.13.10.1211","article-title":"Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls","volume":"13","author":"Kaufman","year":"1999","journal-title":"Genes Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/S1097-2765(02)00696-2","article-title":"The FAD-and O(2)-dependent reaction cycle of Ero1-mediated oxidative protein folding in the endoplasmic reticulum","volume":"10","author":"Tu","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.bbrc.2015.02.004","article-title":"Ca(2+) homeostasis and endoplasmic reticulum (ER) stress: An integrated view of calcium signaling","volume":"460","author":"Krebs","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1016\/j.bbamcr.2014.01.012","article-title":"Endoplasmic reticulum stress associated responses in cancer","volume":"1843","author":"Wang","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/febs.14608","article-title":"Endoplasmic reticulum stress signaling - from basic mechanisms to clinical applications","volume":"286","author":"Almanza","year":"2019","journal-title":"FEBS J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature13119","article-title":"XBP1 promotes triple-negative breast cancer by controlling the HIF1\u03b1 pathway","volume":"508","author":"Chen","year":"2014","journal-title":"Nature"},{"key":"ref_17","first-page":"4278","article-title":"Autocrine control of glioma cells adhesion and migration through IRE1\u03b1-mediated cleavage of SPARC mRNA","volume":"125","author":"Dejeans","year":"2012","journal-title":"J. Cell. Sci."},{"key":"ref_18","first-page":"159","article-title":"Driving Cancer Tumorigenesis and Metastasis Through UPR Signaling","volume":"414","author":"Papaioannou","year":"2018","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","unstructured":"Su, R., Li, Z., Li, H., Song, H., Bao, C., Wei, J., and Cheng, L. (2010). Grp78 promotes the invasion of hepatocellular carcinoma. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-20"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6753","DOI":"10.1007\/s11033-012-1500-8","article-title":"Expressions of GRP78 and Bax associate with differentiation, metastasis and apoptosis in non-small cell lung cancer","volume":"39","author":"Sun","year":"2012","journal-title":"Mol. Biol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1007\/s10620-015-3689-6","article-title":"High Expression of GRP78 Promotes Invasion and Metastases in Patients with Esophageal Squamous Cell Carcinoma","volume":"60","author":"Zhao","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5396","DOI":"10.1158\/0008-5472.CAN-12-0474","article-title":"The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK\/ATF4 pathway","volume":"72","author":"Wang","year":"2012","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"477","DOI":"10.4149\/319_151002N513","article-title":"Prognostic significance of GRP78\/BiP expression in patients with Stage III\/IV hypopharyngeal squamous cell carcinoma","volume":"63","author":"Kaira","year":"2016","journal-title":"Neoplasma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4461","DOI":"10.1158\/0008-5472.CAN-09-0277","article-title":"Endoplasmic reticulum stress triggers XBP-1-mediated up-regulation of an EBV oncoprotein in nasopharyngeal carcinoma","volume":"69","author":"Hsiao","year":"2009","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1002\/hed.21287","article-title":"Positive association of glucose-regulated protein 78 during oral cancer progression and the prognostic value in oral precancerous lesions","volume":"32","author":"Lin","year":"2010","journal-title":"Head Neck"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/hed.24471","article-title":"Decreasing expression of glucose-regulated protein GRP78\/BiP as a significant prognostic predictor in patients with advanced laryngeal squamous cell carcinoma","volume":"38","author":"Kaira","year":"2016","journal-title":"Head Neck"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"588","DOI":"10.4149\/neo_2016_412","article-title":"Expression of ER stress markers (GRP78\/BiP and PERK) in patients with tongue cancer","volume":"63","author":"Kaira","year":"2016","journal-title":"Neoplasma"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S0929-6646(10)60060-5","article-title":"Decreased GRP78 protein expression is a potential prognostic marker of oral squamous cell carcinoma in Taiwan","volume":"109","author":"Huang","year":"2010","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15065","DOI":"10.1074\/jbc.M109.087445","article-title":"Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78\/BiP","volume":"285","author":"Zhang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1002\/hed.23693","article-title":"Hypoxic regulation of the PERK\/ATF4\/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma","volume":"37","author":"Nagelkerke","year":"2015","journal-title":"Head Neck"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1158\/0008-5472.CAN-18-0282","article-title":"DDX3 Activates CBC-eIF3-Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC","volume":"78","author":"Chen","year":"2018","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3493","DOI":"10.1007\/s00018-012-1252-6","article-title":"The eIF2\u03b1 kinases: Their structures and functions","volume":"70","author":"Donnelly","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7198","DOI":"10.1128\/MCB.23.20.7198-7209.2003","article-title":"Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival","volume":"23","author":"Cullinan","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"20108","DOI":"10.1074\/jbc.M314219200","article-title":"PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress","volume":"279","author":"Cullinan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","article-title":"Role of nrf2 in oxidative stress and toxicity","volume":"53","author":"Ma","year":"2013","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1158\/1940-6207.CAPR-12-0401-T","article-title":"Roles of Keap1-Nrf2 system in upper aerodigestive tract carcinogenesis","volume":"6","author":"Ohkoshi","year":"2013","journal-title":"Cancer Prev. Res. (Phila.)"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Tan, D.S.W., Wang, W., Leong, H.S., Sew, P.H., Lau, D.P., Chong, F.T., Krisna, S.S., Lim, T.K.H., and Iyer, N.G. (2014). Tongue carcinoma infrequently harbor common actionable genetic alterations. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-679"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1002\/hed.20430","article-title":"Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas","volume":"28","author":"Stacy","year":"2006","journal-title":"Head Neck"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4333","DOI":"10.3892\/ol.2016.5269","article-title":"Elevated expression of Nrf2 mediates multidrug resistance in CD133+ head and neck squamous cell carcinoma stem cells","volume":"12","author":"Lu","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Huang, C.-F., Zhang, L., Ma, S.-R., Zhao, Z.-L., Wang, W.-M., He, K.-F., Zhao, Y.-F., Zhang, W.-F., Liu, B., and Sun, Z.-J. (2013). Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0083479"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Namani, A., Matiur Rahaman, M., Chen, M., and Tang, X. (2018). Gene-expression signature regulated by the KEAP1-NRF2-CUL3 axis is associated with a poor prognosis in head and neck squamous cell cancer. BMC Cancer, 18.","DOI":"10.1186\/s12885-017-3907-z"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.celrep.2013.03.024","article-title":"Stress-independent activation of XBP1s and\/or ATF6 reveals three functionally diverse ER proteostasis environments","volume":"3","author":"Shoulders","year":"2013","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/1748-717X-6-136","article-title":"GP96 is over-expressed in oral cavity cancer and is a poor prognostic indicator for patients receiving radiotherapy","volume":"6","author":"Lin","year":"2011","journal-title":"Radiat. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1159\/000338613","article-title":"Upregulation of Gp96 correlates with the radiosensitivity and five-year survival rate of nasopharyngeal carcinoma","volume":"74","author":"Zhou","year":"2012","journal-title":"ORL J. Otorhinolaryngol. Relat. Spec."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.oraloncology.2013.01.003","article-title":"Calreticulin, an endoplasmic reticulum-resident protein, is highly expressed and essential for cell proliferation and migration in oral squamous cell carcinoma","volume":"49","author":"Chiang","year":"2013","journal-title":"Oral Oncol."},{"key":"ref_47","first-page":"4043","article-title":"Association of tapasin and HLA class I antigen down-regulation in primary maxillary sinus squamous cell carcinoma lesions with reduced survival of patients","volume":"9","author":"Ogino","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9281","DOI":"10.1158\/0008-5472.CAN-06-0488","article-title":"HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker","volume":"66","author":"Ogino","year":"2006","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/j.1600-0714.2010.00982.x","article-title":"Analysis of differentially expressed proteins in oral squamous cell carcinoma by MALDI-TOF MS","volume":"40","author":"Thiel","year":"2011","journal-title":"J. Oral Pathol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Meyer, M.F., Seuthe, I.M.C., Drebber, U., Siefer, O., Kreppel, M., Klein, M.O., Mikolajczak, S., Klussmann, J.P., Preuss, S.F., and Huebbers, C.U. (2014). Valosin-containing protein (VCP\/p97)-expression correlates with prognosis of HPV- negative oropharyngeal squamous cell carcinoma (OSCC). PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114170"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/cam4.307","article-title":"Recurring DNA copy number gain at chromosome 9p13 plays a role in the activation of multiple candidate oncogenes in progressing oral premalignant lesions","volume":"3","author":"Towle","year":"2014","journal-title":"Cancer Med"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10519","DOI":"10.1073\/pnas.0800939105","article-title":"ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo","volume":"105","author":"Schewe","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1158\/0008-5472.CAN-05-3092","article-title":"Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells","volume":"66","author":"Ranganathan","year":"2006","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.15252\/embj.201490332","article-title":"The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells","volume":"33","author":"Jurkin","year":"2014","journal-title":"EMBO J."},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1101\/gad.964702","article-title":"IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response","volume":"16","author":"Lee","year":"2002","journal-title":"Genes Dev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cca.2018.01.001","article-title":"Decreased cytoplasmic X-box binding protein-1 expression is associated with poor prognosis and overall survival in patients with oral squamous cell carcinoma","volume":"479","author":"Hsu","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.biopha.2015.12.010","article-title":"The molecular mechanisms of XBP-1 gene silencing on IRE1\u03b1-TRAF2-ASK1-JNK pathways in oral squamous cell carcinoma under endoplasmic reticulum stress","volume":"77","author":"Chen","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.7150\/jca.19411","article-title":"Elevated expression of Derlin-1 associates with unfavorable survival time of squamous cell carcinoma of the head and neck and promotes its malignance","volume":"8","author":"Pi","year":"2017","journal-title":"J. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1152\/ajpcell.00258.2014","article-title":"Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 1. ER stress signaling mechanisms: An overview","volume":"307","author":"Dufey","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1158\/2159-8290.CD-14-1490","article-title":"Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis","volume":"5","author":"Chevet","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1593\/neo.13262","article-title":"Amino acid deprivation promotes tumor angiogenesis through the GCN2\/ATF4 pathway","volume":"15","author":"Wang","year":"2013","journal-title":"Neoplasia"},{"key":"ref_63","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_64","doi-asserted-by":"crossref","first-page":"9065","DOI":"10.1038\/srep09065","article-title":"PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2\u2032s mitochondria translocation","volume":"5","author":"Hou","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1534\/g3.115.017269","article-title":"Drosophila melanogaster activating transcription factor 4 regulates glycolysis during endoplasmic reticulum stress","volume":"5","author":"Lee","year":"2015","journal-title":"G3 (Bethesda)"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ceb.2014.10.001","article-title":"Hexosamine pathway and (ER) protein quality control","volume":"33","author":"Denzel","year":"2015","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"27278","DOI":"10.1038\/srep27278","article-title":"Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signaling pathway","volume":"6","author":"Chaveroux","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.semcancer.2015.04.001","article-title":"ER stress and hexosamine pathway during tumourigenesis: A pas de deux?","volume":"33","author":"Vasseur","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1016\/j.celrep.2018.05.006","article-title":"Increased Amino Acid Uptake Supports Autophagy-Deficient Cell Survival upon Glutamine Deprivation","volume":"23","author":"Zhang","year":"2018","journal-title":"Cell Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.cmet.2018.02.009","article-title":"Low-Protein Diet Induces IRE1\u03b1-Dependent Anticancer Immunosurveillance","volume":"27","author":"Bossowski","year":"2018","journal-title":"Cell Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.molmed.2018.05.005","article-title":"Reshaping the Immune Tumor Microenvironment Through IRE1 Signaling","volume":"24","author":"Bossowski","year":"2018","journal-title":"Trends Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.trecan.2017.05.005","article-title":"Emerging Role of the Unfolded Protein Response in Tumor Immunosurveillance","volume":"3","author":"Vanacker","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.it.2018.12.001","article-title":"Endoplasmic Reticulum Stress Responses in Intratumoral Immune Cells: Implications for Cancer Immunotherapy","volume":"40","author":"Song","year":"2019","journal-title":"Trends Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.semcdb.2016.09.005","article-title":"SERPINB3 and B4: From biochemistry to biology","volume":"62","author":"Sun","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1038\/ncomms4729","article-title":"Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3\/B4","volume":"5","author":"Catanzaro","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"6318","DOI":"10.1158\/0008-5472.CAN-14-0798","article-title":"SCCA1\/SERPINB3 promotes oncogenesis and epithelial-mesenchymal transition via the unfolded protein response and IL6 signaling","volume":"74","author":"Sheshadri","year":"2014","journal-title":"Cancer Res."},{"key":"ref_78","first-page":"1343","article-title":"Squamous Cell Carcinoma Antigen-encoding Genes SERPINB3\/B4 as Potentially Useful Markers for the Stratification of HNSCC Tumours","volume":"38","author":"Saidak","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Foy, J.-P., Bazire, L., Ortiz-Cuaran, S., Deneuve, S., Kielbassa, J., Thomas, E., Viari, A., Puisieux, A., Goudot, P., and Bertolus, C. (2017). A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes. BMC Med, 15.","DOI":"10.1186\/s12916-017-0929-y"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1158\/1535-7163.MCT-06-0801","article-title":"Differentially expressed genes in radioresistant nasopharyngeal cancer cells: gp96 and GDF15","volume":"6","author":"Chang","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ijrobp.2010.03.002","article-title":"Proteomics of the radioresistant phenotype in head-and-neck cancer: Gp96 as a novel prediction marker and sensitizing target for radiotherapy","volume":"78","author":"Lin","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_82","first-page":"3016","article-title":"Enhanced expression of calreticulin in the nucleus of radioresistant squamous carcinoma cells in response to ionizing radiation","volume":"55","author":"Ramsamooj","year":"1995","journal-title":"Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.3109\/10715762.2012.724771","article-title":"2-Deoxy-D-glucose and 6-aminonicotinamide-mediated Nrf2 down regulation leads to radiosensitization of malignant cells via abrogation of GSH-mediated defense","volume":"46","author":"Sharma","year":"2012","journal-title":"Free Radic. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.2147\/OTT.S122803","article-title":"Role of Nrf2 signaling pathway in the radiation tolerance of patients with head and neck squamous cell carcinoma: An in vivo and in vitro study","volume":"10","author":"Wang","year":"2017","journal-title":"Onco Targets Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41416-018-0145-3","article-title":"Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma","volume":"119","author":"Xu","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e1431089","DOI":"10.1080\/2162402X.2018.1431089","article-title":"eIF2\u03b1 phosphorylation: A hallmark of immunogenic cell death","volume":"7","author":"Bezu","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/nm.4078","article-title":"The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death","volume":"22","author":"Pozzi","year":"2016","journal-title":"Nat. Med."},{"key":"ref_88","first-page":"4767","article-title":"Cetuximab enhances cisplatin-induced endoplasmic reticulum stress-associated apoptosis in laryngeal squamous cell carcinoma cells by inhibiting expression of TXNDC5","volume":"17","author":"Peng","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_89","first-page":"1708","article-title":"Afatinib down-regulates MCL-1 expression through the PERK-eIF2\u03b1-ATF4 axis and leads to apoptosis in head and neck squamous cell carcinoma","volume":"6","author":"Liu","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3727\/096504016X14586627440192","article-title":"2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells","volume":"24","author":"Sobhakumari","year":"2016","journal-title":"Oncol. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/CCO.0000000000000522","article-title":"Immunotherapy in recurrent and or metastatic squamous cell carcinoma of the head and neck","volume":"31","author":"Peyrade","year":"2019","journal-title":"Curr. Opin. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5068701","DOI":"10.1155\/2018\/5068701","article-title":"The Protein Expression of PDL1 Is Highly Correlated with Those of eIF2\u03b1 and ATF4 in Lung Cancer","volume":"2018","author":"Chang","year":"2018","journal-title":"Dis. Markers"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.molcel.2018.07.030","article-title":"Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1","volume":"71","author":"Cha","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Cole, D.W., Svider, P.F., Shenouda, K.G., Lee, P.B., Yoo, N., McLeod, T.M., Mutchnick, S., Yoo, G.H., Kaufman, R.J., and Callaghan, M.U. (2019). Targeting the unfolded protein response in head and neck and oral cavity cancers. Exp. Cell Res.","DOI":"10.1016\/j.yexcr.2019.04.007"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Liu, R., Zhang, L., Yang, J., Zhang, X., Mikkelsen, R., Song, S., and Zhou, H. (2015). HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress. PLoS ONE, 10.","DOI":"10.1145\/2818302"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.oraloncology.2017.11.018","article-title":"Benzethonium chloride activates ER stress and reduces proliferation in HNSCC","volume":"76","author":"Rayess","year":"2018","journal-title":"Oral Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1021\/acsmedchemlett.5b00133","article-title":"Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop-Dependent Apoptosis","volume":"6","author":"Sidhu","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"31440","DOI":"10.1074\/jbc.M604356200","article-title":"Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa","volume":"281","author":"Fribley","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Su, C.-C., Lee, K.-I., Chen, M.-K., Kuo, C.-Y., Tang, C.-H., and Liu, S.H. (2016). Cantharidin Induced Oral Squamous Cell Carcinoma Cell Apoptosis via the JNK-Regulated Mitochondria and Endoplasmic Reticulum Stress-Related Signaling Pathways. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168095"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5639","DOI":"10.1158\/1078-0432.CCR-12-1213","article-title":"Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck cancer and their activities are enhanced by suppression of Mcl-1 or autophagy","volume":"18","author":"Zang","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.yexcr.2014.08.014","article-title":"Celastrol induces unfolded protein response-dependent cell death in head and neck cancer","volume":"330","author":"Fribley","year":"2015","journal-title":"Exp. Cell Res."},{"key":"ref_102","first-page":"1731","article-title":"Endoplasmic reticulum stress response as a possible mechanism of cyclooxygenase-2-independent anticancer effect of celecoxib","volume":"34","author":"Cha","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1096\/fj.09-135087","article-title":"Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6\/CHOP arm of ER-stress-response pathways","volume":"24","author":"Senkal","year":"2010","journal-title":"FASEB J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"298","DOI":"10.18632\/oncotarget.1628","article-title":"Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress","volume":"5","author":"Lin","year":"2014","journal-title":"Oncotarget"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cbi.2012.01.003","article-title":"The dietary phytochemical 3,3\u2032-diindolylmethane induces G2\/M arrest and apoptosis in oral squamous cell carcinoma by modulating Akt-NF-\u03baB, MAPK and p53 signaling","volume":"195","author":"Weng","year":"2012","journal-title":"Chem. Biol. Interact."},{"key":"ref_106","first-page":"327","article-title":"Emodin induces apoptosis of human tongue squamous cancer SCC-4 cells through reactive oxygen species and mitochondria-dependent pathways","volume":"29","author":"Lin","year":"2009","journal-title":"Anticancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1002\/ijc.28924","article-title":"Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism","volume":"135","author":"Hui","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/s41419-018-0342-2","article-title":"Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells","volume":"9","author":"Ansari","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3892\/or.2013.2457","article-title":"A new curcumin analogue exhibits enhanced antitumor activity in nasopharyngeal carcinoma","volume":"30","author":"Pan","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1016\/j.bbagen.2014.02.022","article-title":"Cell death caused by quinazolinone HMJ-38 challenge in oral carcinoma CAL 27 cells: Dissections of endoplasmic reticulum stress, mitochondrial dysfunction and tumor xenografts","volume":"1840","author":"Lu","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1021\/acsmedchemlett.5b00127","article-title":"Novel Lobophorins Inhibit Oral Cancer Cell Growth and Induce Atf4-and Chop-Dependent Cell Death in Murine Fibroblasts","volume":"6","author":"Cruz","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1002\/jcp.27076","article-title":"PP-22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma cell line CNE-2 by inducing endoplasmic reticulum stress, downregulating STAT3 signaling and modulating the MAPK pathway","volume":"234","author":"Tan","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1177\/1087057111414893","article-title":"Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response","volume":"16","author":"Fribley","year":"2011","journal-title":"J. Biomol. Screen."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3695","DOI":"10.1002\/jcb.23303","article-title":"Reactive oxygen species-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to polydatin-induced apoptosis in human nasopharyngeal carcinoma CNE cells","volume":"112","author":"Liu","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s10495-013-0945-0","article-title":"Resveratrol induced ER expansion and ER caspase-mediated apoptosis in human nasopharyngeal carcinoma cells","volume":"19","author":"Chow","year":"2014","journal-title":"Apoptosis"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"705","DOI":"10.4161\/cbt.6.5.3963","article-title":"Induction of endoplasmic reticulum stress by the pro-apoptotic retinoid N-(4-hydroxyphenyl) retinamide via a reactive oxygen species-dependent mechanism in human head and neck cancer cells","volume":"6","author":"Kadara","year":"2007","journal-title":"Cancer Biol. Ther."},{"key":"ref_117","first-page":"3313","article-title":"Rhein induces apoptosis through induction of endoplasmic reticulum stress and Ca2+-dependent mitochondrial death pathway in human nasopharyngeal carcinoma cells","volume":"27","author":"Lin","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1021\/ml5003234","article-title":"Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response","volume":"5","author":"Flaherty","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Lin, Y.-J., Peng, S.-F., Lin, M.-L., Kuo, C.-L., Lu, K.-W., Liao, C.-L., Ma, Y.-S., Chueh, F.-S., Liu, K.-C., and Yu, F.-S. (2016). Tetrandrine Induces Apoptosis of Human Nasopharyngeal Carcinoma NPC-TW 076 Cells through Reactive Oxygen Species Accompanied by an Endoplasmic Reticulum Stress Signaling Pathway. Molecules, 21.","DOI":"10.3390\/molecules21101353"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1186\/1476-4598-9-283","article-title":"Elimination of head and neck cancer initiating cells through targeting glucose regulated protein 78 signaling","volume":"9","author":"Wu","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.semcancer.2015.04.007","article-title":"Novel roles of the unfolded protein response in the control of tumor development and aggressiveness","volume":"33","author":"Dejeans","year":"2015","journal-title":"Semin. Cancer Biol."},{"key":"ref_122","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_123","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1152\/ajpcell.00292.2014","article-title":"Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 3. Orchestrating the Unfolded Protein Response in oncogenesis: An update","volume":"307","author":"Lebeau","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1038\/onc.2014.292","article-title":"Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor \u03b1-positive breast cancer","volume":"34","author":"Andruska","year":"2015","journal-title":"Oncogene"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/11\/2654\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:54:39Z","timestamp":1760187279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/11\/2654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,30]]},"references-count":124,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["ijms20112654"],"URL":"https:\/\/doi.org\/10.3390\/ijms20112654","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,30]]}}}