{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:29:44Z","timestamp":1790612984334,"version":"4.1.0"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T00:00:00Z","timestamp":1625702400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T00:00:00Z","timestamp":1625702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Frankfurt Research Funding, Medical Faculty, Goethe University"},{"name":"Else Kr\u00f6ner-Forschungskolleg"},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["MU 4216\/1-1"],"award-info":[{"award-number":["MU 4216\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"State of Hessen, LOEWE program"},{"name":"Senckenberg Foundation"},{"name":"University Cancer Center Frankfurt"},{"name":"Johann Wolfgang Goethe-Universit\u00e4t, Frankfurt am Main"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, <jats:italic>ATF4<\/jats:italic> gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.<\/jats:p>","DOI":"10.1038\/s41598-021-93663-1","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T10:04:40Z","timestamp":1625738680000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide"],"prefix":"10.1038","volume":"11","author":[{"given":"Nadja I.","family":"Lorenz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina C. M.","family":"Sittig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Urban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Luisa","family":"Luger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"Engel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"M\u00fcnch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim P.","family":"Steinbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Ronellenfitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,8]]},"reference":[{"key":"93663_CR1","doi-asserted-by":"publisher","first-page":"6892","DOI":"10.1158\/0008-5472.CAN-04-1337","volume":"64","author":"H Ohgaki","year":"2004","unstructured":"Ohgaki, H. et al. Genetic pathways to glioblastoma: a population-based study. Can. Res. 64, 6892\u20136899. https:\/\/doi.org\/10.1158\/0008-5472.CAN-04-1337 (2004).","journal-title":"Can. Res."},{"key":"93663_CR2","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1056\/NEJMoa043330","volume":"352","author":"R Stupp","year":"2005","unstructured":"Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987\u2013996. https:\/\/doi.org\/10.1056\/NEJMoa043330 (2005).","journal-title":"N. Engl. J. Med."},{"key":"93663_CR3","doi-asserted-by":"publisher","first-page":"2306","DOI":"10.1001\/jama.2017.18718","volume":"318","author":"R Stupp","year":"2017","unstructured":"Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA 318, 2306\u20132316. https:\/\/doi.org\/10.1001\/jama.2017.18718 (2017).","journal-title":"JAMA"},{"key":"93663_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bcp.2016.04.008","volume":"118","author":"NM Pe\u00f1arandaFajardo","year":"2016","unstructured":"Pe\u00f1arandaFajardo, N. M., Meijer, C. & Kruyt, F. A. E. The endoplasmic reticulum stress\/unfolded protein response in gliomagenesis, tumor progression and as a therapeutic target in glioblastoma. Biochem. Pharmacol. 118, 1\u20138. https:\/\/doi.org\/10.1016\/j.bcp.2016.04.008 (2016).","journal-title":"Biochem. Pharmacol."},{"key":"93663_CR5","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.15252\/embr.201642195","volume":"17","author":"K Pakos-Zebrucka","year":"2016","unstructured":"Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374\u20131395. https:\/\/doi.org\/10.15252\/embr.201642195 (2016).","journal-title":"EMBO Rep."},{"key":"93663_CR6","doi-asserted-by":"publisher","first-page":"4424","DOI":"10.1038\/onc.2010.191","volume":"29","author":"T Rzymski","year":"2010","unstructured":"Rzymski, T. et al. Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene 29, 4424\u20134435. https:\/\/doi.org\/10.1038\/onc.2010.191 (2010).","journal-title":"Oncogene"},{"key":"93663_CR7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1042\/BST20060007","volume":"34","author":"RC Wek","year":"2006","unstructured":"Wek, R. C., Jiang, H.-Y. & Anthony, T. G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34, 7\u201311. https:\/\/doi.org\/10.1042\/BST20060007 (2006).","journal-title":"Biochem. Soc. Trans."},{"key":"93663_CR8","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","volume":"6","author":"HP Harding","year":"2000","unstructured":"Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099\u20131108. https:\/\/doi.org\/10.1016\/S1097-2765(00)00108-8 (2000).","journal-title":"Mol. Cell"},{"key":"93663_CR9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.biocel.2007.01.020","volume":"40","author":"K Ameri","year":"2008","unstructured":"Ameri, K. & Harris, A. L. Activating transcription factor 4. Int. J. Biochem. Cell Biol. 40, 14\u201321. https:\/\/doi.org\/10.1016\/j.biocel.2007.01.020 (2008).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"93663_CR10","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1038\/emboj.2010.81","volume":"29","author":"J Ye","year":"2010","unstructured":"Ye, J. et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 29, 2082\u20132096. https:\/\/doi.org\/10.1038\/emboj.2010.81 (2010).","journal-title":"EMBO J."},{"key":"93663_CR11","doi-asserted-by":"publisher","first-page":"7469","DOI":"10.1128\/MCB.24.17.7469-7482.2004","volume":"24","author":"JD Blais","year":"2004","unstructured":"Blais, J. D. et al. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol. Cell. Biol. 24, 7469\u20137482. https:\/\/doi.org\/10.1128\/MCB.24.17.7469-7482.2004 (2004).","journal-title":"Mol. Cell. Biol."},{"key":"93663_CR12","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00479-16","author":"R Iurlaro","year":"2017","unstructured":"Iurlaro, R. et al. Glucose deprivation induces ATF4-mediated apoptosis through TRAIL death receptors. Mol. Cell. Biol. https:\/\/doi.org\/10.1128\/MCB.00479-16 (2017).","journal-title":"Mol. Cell. Biol."},{"key":"93663_CR13","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1517\/14728222.2012.728207","volume":"16","author":"DC Singleton","year":"2012","unstructured":"Singleton, D. C. & Harris, A. L. Targeting the ATF4 pathway in cancer therapy. Expert Opin. Ther. Targets 16, 1189\u20131202. https:\/\/doi.org\/10.1517\/14728222.2012.728207 (2012).","journal-title":"Expert Opin. Ther. Targets"},{"key":"93663_CR14","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1158\/0008-5472.CAN-12-3109","volume":"73","author":"C Atkins","year":"2013","unstructured":"Atkins, C. et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Can. Res. 73, 1993\u20132002. https:\/\/doi.org\/10.1158\/0008-5472.CAN-12-3109 (2013).","journal-title":"Can. Res."},{"key":"93663_CR15","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1073\/pnas.1815767116","volume":"116","author":"HH Rabouw","year":"2019","unstructured":"Rabouw, H. H. et al. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation. Proc. Natl. Acad. Sci. USA. 116, 2097\u20132102. https:\/\/doi.org\/10.1073\/pnas.1815767116 (2019).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"93663_CR16","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00498","author":"C Sidrauski","year":"2013","unstructured":"Sidrauski, C. et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife https:\/\/doi.org\/10.7554\/eLife.00498 (2013).","journal-title":"Elife"},{"key":"93663_CR17","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05033","author":"C Sidrauski","year":"2015","unstructured":"Sidrauski, C., McGeachy, A. M., Ingolia, N. T. & Walter, P. The small molecule ISRIB reverses the effects of eIF2\u03b1 phosphorylation on translation and stress granule assembly. Elife https:\/\/doi.org\/10.7554\/eLife.05033 (2015).","journal-title":"Elife"},{"key":"93663_CR18","doi-asserted-by":"publisher","first-page":"5593","DOI":"10.1038\/onc.2017.146","volume":"36","author":"D Chen","year":"2017","unstructured":"Chen, D. et al. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene 36, 5593\u20135608. https:\/\/doi.org\/10.1038\/onc.2017.146 (2017).","journal-title":"Oncogene"},{"key":"93663_CR19","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1002\/ar.23839","volume":"301","author":"Y He","year":"2018","unstructured":"He, Y. et al. Regulation of integrated stress response sensitizes U87MG glioblastoma cells to temozolomide through the mitochondrial apoptosis pathway. Anat. Rec. 301, 1390\u20131397. https:\/\/doi.org\/10.1002\/ar.23839 (2018).","journal-title":"Anat. Rec."},{"key":"93663_CR20","doi-asserted-by":"publisher","first-page":"51164","DOI":"10.18632\/oncotarget.17737","volume":"8","author":"D Chen","year":"2017","unstructured":"Chen, D., Rauh, M., Buchfelder, M., Eyupoglu, I. Y. & Savaskan, N. The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas. Oncotarget 8, 51164\u201351176. https:\/\/doi.org\/10.18632\/oncotarget.17737 (2017).","journal-title":"Oncotarget"},{"key":"93663_CR21","doi-asserted-by":"publisher","first-page":"8177","DOI":"10.1158\/1078-0432.CCR-04-1081","volume":"10","author":"SM Evans","year":"2004","unstructured":"Evans, S. M. et al. Hypoxia is important in the biology and aggression of human glial brain tumors. Clin. Cancer Res. 10, 8177\u20138184. https:\/\/doi.org\/10.1158\/1078-0432.CCR-04-1081 (2004).","journal-title":"Clin. Cancer Res."},{"key":"93663_CR22","doi-asserted-by":"publisher","DOI":"10.3390\/cells6040045","author":"AR Monteiro","year":"2017","unstructured":"Monteiro, A. R., Hill, R., Pilkington, G. J. & Madureira, P. A. The role of hypoxia in glioblastoma invasion. Cells https:\/\/doi.org\/10.3390\/cells6040045 (2017).","journal-title":"Cells"},{"key":"93663_CR23","doi-asserted-by":"publisher","first-page":"368","DOI":"10.18632\/oncotarget.26569","volume":"10","author":"S Moeckel","year":"2019","unstructured":"Moeckel, S. et al. ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs). Oncotarget 10, 368\u2013382. https:\/\/doi.org\/10.18632\/oncotarget.26569 (2019).","journal-title":"Oncotarget"},{"key":"93663_CR24","doi-asserted-by":"publisher","first-page":"43820","DOI":"10.18632\/oncotarget.9907","volume":"7","author":"JL Weatherbee","year":"2016","unstructured":"Weatherbee, J. L., Kraus, J.-L. & Ross, A. H. ER stress in temozolomide-treated glioblastomas interferes with DNA repair and induces apoptosis. Oncotarget 7, 43820\u201343834. https:\/\/doi.org\/10.18632\/oncotarget.9907 (2016).","journal-title":"Oncotarget"},{"key":"93663_CR25","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/ncb2738","volume":"15","author":"J Han","year":"2013","unstructured":"Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481\u2013490. https:\/\/doi.org\/10.1038\/ncb2738 (2013).","journal-title":"Nat. Cell Biol."},{"key":"93663_CR26","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1038\/sj.emboj.7600596","volume":"24","author":"N Ohoka","year":"2005","unstructured":"Ohoka, N., Yoshii, S., Hattori, T., Onozaki, K. & Hayashi, H. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J. 24, 1243\u20131255. https:\/\/doi.org\/10.1038\/sj.emboj.7600596 (2005).","journal-title":"EMBO J."},{"key":"93663_CR27","doi-asserted-by":"publisher","first-page":"6091","DOI":"10.1074\/jbc.M109.014092","volume":"285","author":"JL Armstrong","year":"2010","unstructured":"Armstrong, J. L., Flockhart, R., Veal, G. J., Lovat, P. E. & Redfern, C. P. F. Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J. Biol. Chem. 285, 6091\u20136100. https:\/\/doi.org\/10.1074\/jbc.M109.014092 (2010).","journal-title":"J. Biol. Chem."},{"key":"93663_CR28","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1091\/mbc.E16-01-0039","volume":"27","author":"ME Fusakio","year":"2016","unstructured":"Fusakio, M. E. et al. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol. Biol. Cell 27, 1536\u20131551. https:\/\/doi.org\/10.1091\/mbc.E16-01-0039 (2016).","journal-title":"Mol. Biol. Cell"},{"key":"93663_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.318","volume":"7","author":"S Jawhari","year":"2016","unstructured":"Jawhari, S., Ratinaud, M.-H. & Verdier, M. Glioblastoma, hypoxia and autophagy: A survival-prone \u201cm\u00e9nage-\u00e0-trois\u201d. Cell Death Dis. 7, e2434. https:\/\/doi.org\/10.1038\/cddis.2016.318 (2016).","journal-title":"Cell Death Dis."},{"key":"93663_CR30","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/sj.cdd.4401252","volume":"10","author":"JP Steinbach","year":"2003","unstructured":"Steinbach, J. P., Wolburg, H., Klumpp, A., Probst, H. & Weller, M. Hypoxia-induced cell death in human malignant glioma cells: energy deprivation promotes decoupling of mitochondrial cytochrome c release from caspase processing and necrotic cell death. Cell Death Differ. 10, 823\u2013832. https:\/\/doi.org\/10.1038\/sj.cdd.4401252 (2003).","journal-title":"Cell Death Differ."},{"key":"93663_CR31","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.1074\/jbc.RA118.006993","volume":"294","author":"I Bruns","year":"2019","unstructured":"Bruns, I. et al. Disruption of peroxisome proliferator-activated receptor \u03b3 coactivator (PGC)-1\u03b1 reverts key features of the neoplastic phenotype of glioma cells. J. Biol. Chem. 294, 3037\u20133050. https:\/\/doi.org\/10.1074\/jbc.RA118.006993 (2019).","journal-title":"J. Biol. Chem."},{"key":"93663_CR32","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.molcel.2019.11.010","volume":"77","author":"K Klann","year":"2020","unstructured":"Klann, K., Tascher, G. & M\u00fcnch, C. Functional translatome proteomics reveal converging and dose-dependent regulation by mTORC1 and eIF2\u03b1. Mol. Cell 77, 913-925.e4. https:\/\/doi.org\/10.1016\/j.molcel.2019.11.010 (2020).","journal-title":"Mol. Cell"},{"key":"93663_CR33","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.1093\/brain\/awx196","volume":"140","author":"A-L Thiepold","year":"2017","unstructured":"Thiepold, A.-L. et al. Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death. Brain 140, 2623\u20132638. https:\/\/doi.org\/10.1093\/brain\/awx196 (2017).","journal-title":"Brain"},{"key":"93663_CR34","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11060804","author":"J Jiang","year":"2019","unstructured":"Jiang, J., Srivastava, S. & Zhang, J. Starve cancer cells of glutamine: Break the spell or make a hungry monster?. Cancers https:\/\/doi.org\/10.3390\/cancers11060804 (2019).","journal-title":"Cancers"},{"key":"93663_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.49","volume":"6","author":"M Halliday","year":"2015","unstructured":"Halliday, M. et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 6, e1672. https:\/\/doi.org\/10.1038\/cddis.2015.49 (2015).","journal-title":"Cell Death Dis."},{"key":"93663_CR36","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1038\/s41419-019-1934-1","volume":"10","author":"NM Pe\u00f1aranda-Fajardo","year":"2019","unstructured":"Pe\u00f1aranda-Fajardo, N. M. et al. ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation. Cell Death Dis. 10, 690. https:\/\/doi.org\/10.1038\/s41419-019-1934-1 (2019).","journal-title":"Cell Death Dis."},{"key":"93663_CR37","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1186\/s13046-019-1413-7","volume":"38","author":"Y Chen","year":"2019","unstructured":"Chen, Y. et al. Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK\/ATF4\/HSPA5 pathway in glioma cells. J. Exp. Clin. Cancer Res. 38, 402. https:\/\/doi.org\/10.1186\/s13046-019-1413-7 (2019).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"93663_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2020.1827780","volume":"1","author":"S Zielke","year":"2020","unstructured":"Zielke, S. et al. ATF4 links ER stress with reticulophagy in glioblastoma cells. Autophagy 1, 1\u201317. https:\/\/doi.org\/10.1080\/15548627.2020.1827780 (2020).","journal-title":"Autophagy"},{"key":"93663_CR39","doi-asserted-by":"publisher","first-page":"8233","DOI":"10.1038\/sj.onc.1207198","volume":"22","author":"J Wischhusen","year":"2003","unstructured":"Wischhusen, J., Naumann, U., Ohgaki, H., Rastinejad, F. & Weller, M. CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. Oncogene 22, 8233\u20138245. https:\/\/doi.org\/10.1038\/sj.onc.1207198 (2003).","journal-title":"Oncogene"},{"key":"93663_CR40","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1111\/j.1471-4159.2009.06027.x","volume":"109","author":"C Eckerich","year":"2009","unstructured":"Eckerich, C. et al. RON receptor tyrosine kinase in human gliomas: Expression, function, and identification of a novel soluble splice variant. J. Neurochem. 109, 969\u2013980. https:\/\/doi.org\/10.1111\/j.1471-4159.2009.06027.x (2009).","journal-title":"J. Neurochem."},{"key":"93663_CR41","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1111\/j.1750-3639.1999.tb00536.x","volume":"9","author":"N Ishii","year":"1999","unstructured":"Ishii, N. et al. Frequent co-alterations of TP53, p16\/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol. 9, 469\u2013479. https:\/\/doi.org\/10.1111\/j.1750-3639.1999.tb00536.x (1999).","journal-title":"Brain Pathol."},{"key":"93663_CR42","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1093\/brain\/awp093","volume":"132","author":"MW Ronellenfitsch","year":"2009","unstructured":"Ronellenfitsch, M. W. et al. Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death. Brain 132, 1509\u20131522. https:\/\/doi.org\/10.1093\/brain\/awp093 (2009).","journal-title":"Brain"},{"key":"93663_CR43","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1111\/j.1471-4159.2005.03583.x","volume":"96","author":"M Hermisson","year":"2006","unstructured":"Hermisson, M. et al. O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J. Neurochem. 96, 766\u2013776. https:\/\/doi.org\/10.1111\/j.1471-4159.2005.03583.x (2006).","journal-title":"J. Neurochem."},{"key":"93663_CR44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063527","volume":"8","author":"D Gramatzki","year":"2013","unstructured":"Gramatzki, D. et al. Glioma cell death induced by irradiation or alkylating agent chemotherapy is independent of the intrinsic ceramide pathway. PLoS ONE 8, e63527. https:\/\/doi.org\/10.1371\/journal.pone.0063527 (2013).","journal-title":"PLoS ONE"},{"key":"93663_CR45","doi-asserted-by":"publisher","first-page":"3764","DOI":"10.1038\/onc.2011.530","volume":"31","author":"C Wanka","year":"2012","unstructured":"Wanka, C. et al. Synthesis of cytochrome C oxidase 2: A p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death. Oncogene 31, 3764\u20133776. https:\/\/doi.org\/10.1038\/onc.2011.530 (2012).","journal-title":"Oncogene"},{"key":"93663_CR46","doi-asserted-by":"publisher","first-page":"0034","DOI":"10.1186\/gb-2002-3-7-research0034","volume":"3","author":"J Vandesompele","year":"2002","unstructured":"Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, 0034. https:\/\/doi.org\/10.1186\/gb-2002-3-7-research0034 (2002).","journal-title":"Genome Biol."},{"key":"93663_CR47","first-page":"1114","volume":"20","author":"JE Grady","year":"1960","unstructured":"Grady, J. E., Lummis, W. L. & Smith, C. G. An improved tissue culture assay. III. Alternate methods for measuring cell growth. Cancer Res. 20, 1114\u20131117 (1960).","journal-title":"Cancer Res."},{"key":"93663_CR48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094921","volume":"9","author":"S Fischer","year":"2014","unstructured":"Fischer, S. et al. Hypoxia enhances the antiglioma cytotoxicity of B10, a glycosylated derivative of betulinic acid. PLoS ONE 9, e94921. https:\/\/doi.org\/10.1371\/journal.pone.0094921 (2014).","journal-title":"PLoS ONE"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93663-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93663-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93663-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T11:07:24Z","timestamp":1670065644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-93663-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,8]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["93663"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-93663-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,8]]},"assertion":[{"value":"18 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"JPS has a consulting or advisory board membership with, or has received honoraria or travel or accommodation expenses from Abbvie, Medac, Novocure, Roche, and UCB. MWR has received research funding from UCB. All other authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14161"}}