{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:37:05Z","timestamp":1792089425885,"version":"4.4.0"},"reference-count":87,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012155","name":"National Institute for Medical Research Development","doi-asserted-by":"publisher","award":["943267"],"award-info":[{"award-number":["943267"]}],"id":[{"id":"10.13039\/501100012155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008794","name":"Research Manitoba","doi-asserted-by":"publisher","award":["47929"],"award-info":[{"award-number":["47929"]}],"id":[{"id":"10.13039\/100008794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva\u2013TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2\u03b1 inhibitor salubrinal. Simva\u2013TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva\u2013TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2\u03b1 (eIF2\u03b1) phosphorylation, and inhibited autophagic flux (accumulation of LC3\u03b2-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva\u2013TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)\u03b2-II\/LC3\u03b2-I ratio in U87 cells, while salubrinal did not affect the Simva\u2013TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva\u2013TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3\u03b2-II\/LC3\u03b2-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva\u2013TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells.<\/jats:p>","DOI":"10.3390\/cells9112339","type":"journal-article","created":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T20:51:00Z","timestamp":1603399860000},"page":"2339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-9221","authenticated-orcid":false,"given":"Sanaz","family":"Dastghaib","sequence":"first","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran"},{"name":"Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahla","family":"Shojaei","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohreh","family":"Mostafavi-Pour","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran"},{"name":"Maternal-Fetal Medicine Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2904-2306","authenticated-orcid":false,"given":"Pawan","family":"Sharma","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane &amp; Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Patterson","sequence":"additional","affiliation":[{"name":"Orinove, Newbury Park, CA 91320, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8610-8375","authenticated-orcid":false,"given":"Afshin","family":"Samali","sequence":"additional","affiliation":[{"name":"Apoptosis Research Centre, National University of Ireland, H91 W2TY Galway, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9717-0473","authenticated-orcid":false,"given":"Pooneh","family":"Mokarram","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran"},{"name":"Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran"},{"name":"Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5948-508X","authenticated-orcid":false,"given":"Saeid","family":"Ghavami","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"},{"name":"Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran"},{"name":"Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s11060-019-03357-y","article-title":"Whole brain apparent diffusion coefficient measurements correlate with survival in glioblastoma patients","volume":"146","author":"Rulseh","year":"2020","journal-title":"J. Neuroncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/nox158","article-title":"CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010\u20132014","volume":"19","author":"Ostrom","year":"2017","journal-title":"Neuro Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Samiei, E., Seyfoori, A., Toyota, B., Ghavami, S., and Akbari, M. (2020). Investigating Programmed Cell Death and Tumor Invasion in a Three-Dimensional (3D) Microfluidic Model of Glioblastoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093162"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"22493","DOI":"10.1002\/jcp.28813","article-title":"Neuropathological and genomic characterization of glioblastoma-induced rat model: How similar is it to humans for targeted therapy?","volume":"234","author":"Sharifzad","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sharifzad, F., Mardpour, S., Mardpour, S., Fakharian, E., Taghikhani, A., Sharifzad, A., Kiani, S., Heydarian, Y., Los, M.J., and Azizi, Z. (2020). HSP70\/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM). Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints202002.0364.v1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/neuonc\/nou087","article-title":"The epidemiology of glioma in adults: A \u201cstate of the science\u201d review","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1007\/s12035-013-8593-5","article-title":"Systematic review of protein biomarkers of invasive behavior in glioblastoma","volume":"49","author":"Sayegh","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41420-018-0115-9","article-title":"Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells","volume":"4","author":"Moghadam","year":"2018","journal-title":"Cell Death Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.drup.2016.02.001","article-title":"Could drugs inhibiting the mevalonate pathway also target cancer stem cells?","volume":"25","author":"Likus","year":"2016","journal-title":"Drug Resist. Updat"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"165968","DOI":"10.1016\/j.bbadis.2020.165968","article-title":"Pleiotropic effects of statins: A focus on cancer","volume":"1866","author":"Ahmadi","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1093\/cvr\/cvn160","article-title":"HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression","volume":"80","author":"Chen","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.canep.2014.09.010","article-title":"Statin use and survival following glioblastoma multiforme","volume":"38","author":"Gaist","year":"2014","journal-title":"Cancer Epidemiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1056\/NEJMoa1201735","article-title":"Statin use and reduced cancer-related mortality","volume":"367","author":"Nielsen","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1517\/14740331003662620","article-title":"Statin use and cancer risk: A comprehensive review","volume":"9","author":"Boudreau","year":"2010","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.3892\/or.2015.3741","article-title":"Statins are potential anticancerous agents (review)","volume":"33","author":"Altwairgi","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1136\/jim-2018-000874","article-title":"Statins: A new approach to combat temozolomide chemoresistance in glioblastoma","volume":"66","author":"Shojaei","year":"2018","journal-title":"J. Investig. Med."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cell.2014.02.049","article-title":"To be or not to be? How selective autophagy and cell death govern cell fate","volume":"157","author":"Green","year":"2014","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tibs.2015.01.002","article-title":"UPR, autophagy, and mitochondria crosstalk underlies the ER stress response","volume":"40","author":"Senft","year":"2015","journal-title":"Trends Biochem. Sci."},{"key":"ref_21","first-page":"1","article-title":"ER stress and UPR activation in glioblastoma: Identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation","volume":"10","author":"Meijer","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.pharmthera.2017.10.017","article-title":"Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response","volume":"184","author":"Mehrpour","year":"2018","journal-title":"Pharm. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.trecan.2016.03.007","article-title":"Endoplasmic reticulum stress and the hallmarks of cancer","volume":"2","author":"Urra","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_24","first-page":"43","article-title":"Autophagy in breast cancer metastatic dormancy: Tumor suppressing or tumor promoting functions?","volume":"5","author":"Flynn","year":"2019","journal-title":"J. Cancer Metastasis Treat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1101\/gad.17558811","article-title":"The dynamic nature of autophagy in cancer","volume":"25","author":"Kimmelman","year":"2011","journal-title":"Genes Dev."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ghavami, S., Mutawe, M.M., Sharma, P., Yeganeh, B., McNeill, K.D., Klonisch, T., Unruh, H., Kashani, H.H., Schaafsma, D., and Los, M. (2011). Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: A dual role for p53. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016523"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1080\/21505594.2020.1780088","article-title":"Autophagy and SARS-CoV-2 infection: Apossible smart targeting of the autophagy pathway","volume":"11","author":"Shojaei","year":"2020","journal-title":"Virulence"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/7651_2017_84","article-title":"Simultaneous Detection of Autophagy and Epithelial to Mesenchymal Transition in the Non-small Cell Lung Cancer Cells","volume":"1854","author":"Alizadeh","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hsu, S.-K., Chiu, C.-C., Dahms, H.-U., Chou, C.-K., Cheng, C.-M., Chang, W.-T., Cheng, K.-C., Wang, H.-M.D., and Lin, I. (2019). Unfolded protein response (UPR) in survival, dormancy, immunosuppression, metastasis, and treatments of cancer cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102518"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"173288","DOI":"10.1016\/j.ejphar.2020.173288","article-title":"Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?","volume":"882","author":"Sureda","year":"2020","journal-title":"Eur. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1080\/21505594.2019.1605803","article-title":"The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections","volume":"10","author":"Mehrbod","year":"2019","journal-title":"Virulence"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/j.1749-6632.2012.06739.x","article-title":"Unfolded protein response to autophagy as a promising druggable target for anticancer therapy","volume":"1271","author":"Suh","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1038\/s41467-018-05763-8","article-title":"Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy","volume":"9","author":"Logue","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"L493","DOI":"10.1152\/ajplung.00372.2017","article-title":"Autophagy and the unfolded protein response promote profibrotic effects of TGF-beta1 in human lung fibroblasts","volume":"314","author":"Ghavami","year":"2018","journal-title":"Am. J. Physiol Lung Cell. Mol. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13225","DOI":"10.3748\/wjg.v21.i47.13225","article-title":"Hepatitis B and C virus-induced hepatitis: Apoptosis, autophagy, and unfolded protein response","volume":"21","author":"Yeganeh","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e330","DOI":"10.1038\/cddis.2012.61","article-title":"Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts","volume":"3","author":"Ghavami","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.bbamcr.2014.03.006","article-title":"Airway mesenchymal cell death by mevalonate cascade inhibition: Integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins","volume":"1843","author":"Ghavami","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1159\/000362457","article-title":"Endoplasmic reticulum stress induces epithelial-mesenchymal transition through autophagy via activation of c-Src kinase","volume":"126","author":"Moon","year":"2014","journal-title":"Nephron Exp. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/cdd.2014.183","article-title":"Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma","volume":"22","author":"Corazzari","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1017\/cjn.2018.255","article-title":"08 Inhibition of autophagy by mevalonate pathway inhibitors, a new therapeutic approach to sensitize glioblastoma cells to temozolomide induced apoptosis","volume":"45","author":"Shojaei","year":"2018","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1111\/febs.15069","article-title":"Simvastatin increases temozolomide-induced cell death by targeting the fusion of autophagosomes and lysosomes","volume":"287","author":"Shojaei","year":"2020","journal-title":"FEBS J."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Dastghaib, S., Kumar, P.S., Aftabi, S., Damera, G., Dalvand, A., Sepanjnia, A., Kiumarsi, M., Aghanoori, M.R., Sohal, S.S., and Ande, S.R. (2020). Mechanisms Targeting the Unfolded Protein Response in Asthma. Am. J. Respir. Cell Mol. Biol., in press.","DOI":"10.1165\/rcmb.2019-0235TR"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sheikholeslami, K., Ali Sher, A., Lockman, S., Kroft, D., Ganjibakhsh, M., Nejati-Koshki, K., Shojaei, S., Ghavami, S., and Rastegar, M. (2019). Simvastatin induces apoptosis in medulloblastoma brain tumor cells via mevalonate cascade prenylation substrates. Cancers, 11.","DOI":"10.3390\/cancers11070994"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/jbm.b.31723","article-title":"Comparison of MTT assay, flow cytometry, and RT-PCR in the evaluation of cytotoxicity of five prosthodontic materials","volume":"95","author":"Wang","year":"2010","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Van Tonder, A., Joubert, A.M., and Cromarty, A.D. (2015). Limitations of the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay when compared to three commonly used cell enumeration assays. BMC Res. Notes, 8.","DOI":"10.1186\/s13104-015-1000-8"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"172616","DOI":"10.1016\/j.ejphar.2019.172616","article-title":"Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition","volume":"862","author":"Emami","year":"2019","journal-title":"Eur. J. Pharm."},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/hsz-2013-0174","article-title":"Stressed to death\u2014Mechanisms of ER stress-induced cell death","volume":"395","author":"Sovolyova","year":"2014","journal-title":"Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1016\/j.febslet.2012.10.002","article-title":"NOXA contributes to the sensitivity of PERK-deficient cells to ER stress","volume":"586","author":"Gupta","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_51","first-page":"1390","article-title":"The regulatory activity of autophagy in conjunctival fibroblasts and its possible role in vernal keratoconjunctivitis","volume":"17","author":"Brun","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1165\/rcmb.2019-0141LE","article-title":"Pharmacologic Inhibition of Vacuolar H(+)ATPase Attenuates Features of Severe Asthma in Mice","volume":"62","author":"McAlinden","year":"2020","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1165\/rcmb.2018-0169OC","article-title":"Autophagy Activation in Asthma Airways Remodeling","volume":"60","author":"McAlinden","year":"2019","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.tibs.2016.09.008","article-title":"Emerging mechanisms in initiating and terminating autophagy","volume":"42","author":"Antonioli","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Golbabapour, S., Bagheri-Lankarani, K., Ghavami, S., and Geramizadeh, B. (2019). Autoimmune Hepatitis and Stellate Cells; an Insight into the Role of Autophagy. Curr. Med. Chem.","DOI":"10.2174\/0929867326666190402120231"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"721","DOI":"10.4161\/cbt.5.7.3120","article-title":"ER stress and cancer","volume":"5","author":"Lee","year":"2006","journal-title":"Cancer Biol. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1756-8722-4-8","article-title":"Unfolded protein response in cancer: The physician\u2019s perspective","volume":"4","author":"Li","year":"2011","journal-title":"J. Hematol. Oncol."},{"key":"ref_58","first-page":"91","article-title":"Induction of autophagy: Role of endoplasmic reticulum stress and unfolded protein response","volume":"Volume 7","author":"Hayat","year":"2015","journal-title":"Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ejphar.2009.06.064","article-title":"Targeting the endoplasmic reticulum-stress response as an anticancer strategy","volume":"625","author":"Healy","year":"2009","journal-title":"Eur. J. Pharm."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1291\/hypres.31.1977","article-title":"Inhibition of cardiac remodeling by pravastatin is associated with amelioration of endoplasmic reticulum stress","volume":"31","author":"Zhao","year":"2008","journal-title":"Hypertens. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1139\/Y09-085","article-title":"Atorvastatin mediates increases in intralesional BAX and BAK expression in human end-stage abdominal aortic aneurysms","volume":"87","author":"Schweitzer","year":"2009","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2710693","DOI":"10.1155\/2019\/2710693","article-title":"Lovastatin enhances cytotoxicity of temozolomide via impairing autophagic flux in glioblastoma cells","volume":"2019","author":"Zhu","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"408","DOI":"10.3389\/fphar.2020.00408","article-title":"Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy","volume":"11","author":"Liu","year":"2020","journal-title":"Front. Pharm."},{"key":"ref_64","first-page":"867","article-title":"Coxsackievirus B3 Infection Triggers Autophagy through 3 Pathways of Endoplasmic Reticulum Stress","volume":"31","author":"Luo","year":"2018","journal-title":"Biomed. Environ. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/s41419-018-0930-1","article-title":"Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells","volume":"9","author":"Kim","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.3892\/ijmm.2017.3145","article-title":"Autophagy mediated by endoplasmic reticulum stress enhances the caffeine-induced apoptosis of hepatic stellate cells","volume":"40","author":"Li","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.bbrc.2014.11.076","article-title":"A close connection between the PERK and IRE arms of the UPR and the transcriptional regulation of autophagy","volume":"456","author":"Deegan","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"772","DOI":"10.3892\/ijmm.2014.1822","article-title":"Connecting endoplasmic reticulum stress to autophagy through IRE1\/JNK\/beclin-1 in breast cancer cells","volume":"34","author":"Cheng","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/hmg\/ddr445","article-title":"IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux","volume":"21","author":"Lee","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1111\/febs.15144","article-title":"The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK","volume":"287","author":"Hu","year":"2020","journal-title":"FEBS J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.virol.2019.08.029","article-title":"Seneca valley virus activates autophagy through the PERK and ATF6 UPR pathways","volume":"537","author":"Hou","year":"2019","journal-title":"Virology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12964-019-0353-3","article-title":"ATG5 and ATG7 induced autophagy interplays with UPR via PERK signaling","volume":"17","author":"Zheng","year":"2019","journal-title":"Cell Commun. Signal."},{"key":"ref_73","first-page":"854","article-title":"Downregulation of miR-221\/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of p53 status","volume":"27","author":"Chen","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_74","unstructured":"Kawtharani, Z. (2020). The Antitumor Effect of the Atypical Retinoid ST1926 in Human Glioblastoma. [Master\u2019s Thesis, American University of Beirut]."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/sj.onc.1209785","article-title":"Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O 6-methylguanine","volume":"26","author":"Roos","year":"2007","journal-title":"Oncogene"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11060-010-0283-9","article-title":"Effect of aberrant p53 function on temozolomide sensitivity of glioma cell lines and brain tumor initiating cells from glioblastoma","volume":"102","author":"Blough","year":"2011","journal-title":"J. Neuro Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.gendis.2016.04.007","article-title":"Temozolomide resistance in glioblastoma multiforme","volume":"3","author":"Lee","year":"2016","journal-title":"Genes Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"L420","DOI":"10.1152\/ajplung.00312.2011","article-title":"Geranylgeranyl transferase 1 modulates autophagy and apoptosis in human airway smooth muscle","volume":"302","author":"Ghavami","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"810","DOI":"10.4161\/auto.6486","article-title":"A dual role of p53 in the control of autophagy","volume":"4","author":"Tasdemir","year":"2008","journal-title":"Autophagy"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"19990","DOI":"10.18632\/oncotarget.4598","article-title":"Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1\u03b1\/XBP1 pathway","volume":"6","author":"Namba","year":"2015","journal-title":"Oncotarget"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Fusee, L.T.S., Marin, M., Fahraeus, R., and Lopez, I. (2020). Alternative Mechanisms of p53 Action During the Unfolded Protein Response. Cancers, 12.","DOI":"10.3390\/cancers12020401"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.bbamcr.2018.02.007","article-title":"Autophagy modulates transforming growth factor beta 1 induced epithelial to mesenchymal transition in non-small cell lung cancer cells","volume":"1865","author":"Alizadeh","year":"2018","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejphar.2006.11.010","article-title":"Cytotoxic effects of intra and extracellular zinc chelation on human breast cancer cells","volume":"557","author":"Hashemi","year":"2007","journal-title":"Eur. J. Pharm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1111\/j.1582-4934.2008.00129.x","article-title":"Brevinin-2R(1) semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway","volume":"12","author":"Ghavami","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.bbamcr.2009.12.005","article-title":"Statin-triggered cell death in primary human lung mesenchymal cells involves p53-PUMA and release of Smac and Omi but not cytochrome c","volume":"1803","author":"Ghavami","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"78516","DOI":"10.18632\/oncotarget.12392","article-title":"Inhibition of autophagy inhibits the conversion of cardiac fibroblasts to cardiac myofibroblasts","volume":"7","author":"Gupta","year":"2016","journal-title":"Oncotarget"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.bbamcr.2009.01.002","article-title":"Role of BNIP3 in TNF-induced cell death--TNF upregulates BNIP3 expression","volume":"1793","author":"Ghavami","year":"2009","journal-title":"Biochim. Biophys. Acta"}],"updated-by":[{"DOI":"10.3390\/cells13080722","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000}}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/11\/2339\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T14:03:13Z","timestamp":1754229793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/11\/2339"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,22]]},"references-count":87,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cells9112339"],"URL":"https:\/\/doi.org\/10.3390\/cells9112339","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,22]]}}}