Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJYCREE)

• DOT Name: X-box-binding protein 1
• Synonyms: XBP-1; Tax-responsive element-binding protein 5; TREB-5
• Gene Name: XBP1
• UniProt ID: XBP1_HUMAN
• PDB ID: 6R5Q; 6R6G; 6R6P; 6R7Q
• Pfam ID: PF07716
• Sequence:
  MVVVAAAPNPADGTPKVLLLSGQPASAAGAPAGQALPLMVPAQRGASPEAASGGLPQARK
  RQRLTHLSPEEKALRRKLKNRVAAQTARDRKKARMSELEQQVVDLEEENQKLLLENQLLR
  EKTHGLVVENQELRQRLGMDALVAEEEAEAKGNEVRPVAGSAESAALRLRAPLQQVQAQL
  SPLQNISPWILAVLTLQIQSLISCWAFWTTWTQSCSSNALPQSLPAWRSSQRSTQKDPVP
  YQPPFLCQWGRHQPSWKPLMN
• Function: Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland. Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins. Modulates the cellular response to ER stress in a PIK3R-dependent manner. Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes. Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Functions also as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention; [Isoform 1]: Plays a role in the unconventional cytoplasmic splicing processing of its own mRNA triggered by the endoplasmic reticulum (ER) transmembrane endoribonuclease ERN1: upon ER stress, the emerging XBP1 polypeptide chain, as part of a mRNA-ribosome-nascent chain (R-RNC) complex, cotranslationally recruits its own unprocessed mRNA through transient docking to the ER membrane and translational pausing, therefore facilitating efficient IRE1-mediated XBP1 mRNA isoform 2 production. In endothelial cells (EC), associated with KDR, promotes IRE1-mediated XBP1 mRNA isoform 2 productions in a vascular endothelial growth factor (VEGF)-dependent manner, leading to EC proliferation and angiogenesis. Functions as a negative feed-back regulator of the potent transcription factor XBP1 isoform 2 protein levels through proteasome-mediated degradation, thus preventing the constitutive activation of the ER stress response signaling pathway. Inhibits the transactivation activity of XBP1 isoform 2 in myeloma cells. Acts as a weak transcriptional factor. Together with HDAC3, contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to EC survival under disturbed flow/oxidative stress. Binds to the ER stress response element (ERSE) upon ER stress. Binds to the consensus 5'-GATGACGTG[TG]N(3)[AT]T-3' sequence related to cAMP responsive element (CRE)-like sequences. Binds the Tax-responsive element (TRE) present in the long terminal repeat (LTR) of T-cell leukemia virus type 1 (HTLV-I) and to the TPA response elements (TRE). Associates preferentially to the HDAC3 gene promoter region in a static flow-dependent manner. Binds to the CDH5/VE-cadherin gene promoter region ; [Isoform 2]: Functions as a stress-inducible potent transcriptional activator during endoplasmic reticulum (ER) stress by inducing unfolded protein response (UPR) target genes via binding to the UPR element (UPRE). Up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanism, respectively, in order to maintain the homeostasis of the ER under ER stress. Plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation. Induces phospholipid biosynthesis and ER expansion. Contributes to the VEGF-induced endothelial cell (EC) growth and proliferation in a Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression. Promotes umbilical vein EC apoptosis and atherosclerotisis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions. Involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation. Plays a role as an oncogene by promoting tumor progression: stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells. Involved in adipocyte differentiation by regulating lipogenic gene expression during lactation. Plays a role in the survival of both dopaminergic neurons of the substantia nigra pars compacta (SNpc), by maintaining protein homeostasis and of myeloma cells. Increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. Improves also glucose homeostasis in an ER stress- and/or insulin-independent manner through both binding and proteasome-induced degradation of the transcription factor FOXO1, hence resulting in suppression of gluconeogenic genes expression and in a reduction of blood glucose levels. Controls the induction of de novo fatty acid synthesis in hepatocytes by regulating the expression of a subset of lipogenic genes in an ER stress- and UPR-independent manner. Associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner. Binds to the BECN1 gene promoter region. Binds to the CDH5/VE-cadherin gene promoter region. Binds to the ER stress response element (ERSE) upon ER stress. Binds to the 5'-CCACG-3' motif in the PPARG promoter.
• Tissue Specificity: Expressed in plasma cells in rheumatoid synovium . Over-expressed in primary breast cancer and metastatic breast cancer cells . Isoform 1 and isoform 2 are expressed at higher level in proliferating as compared to confluent quiescent endothelial cells .
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Lipid and atherosclerosis (hsa05417)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	DMPWB8G	Investigative	X-box-binding protein 1 decreases the response to substance of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.	[69]

75 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of X-box-binding protein 1.	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of X-box-binding protein 1.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of X-box-binding protein 1.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of X-box-binding protein 1.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of X-box-binding protein 1.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of X-box-binding protein 1.	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of X-box-binding protein 1.	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of X-box-binding protein 1.	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of X-box-binding protein 1.	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of X-box-binding protein 1.	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of X-box-binding protein 1.	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of X-box-binding protein 1.	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of X-box-binding protein 1.	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of X-box-binding protein 1.	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of X-box-binding protein 1.	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of X-box-binding protein 1.	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of X-box-binding protein 1.	[5]
Bortezomib	DMNO38U	Approved	Bortezomib increases the activity of X-box-binding protein 1.	[16]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the splicing of X-box-binding protein 1.	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the activity of X-box-binding protein 1.	[18]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of X-box-binding protein 1.	[19]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of X-box-binding protein 1.	[2]
Fenofibrate	DMFKXDY	Approved	Fenofibrate affects the activity of X-box-binding protein 1.	[2]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the activity of X-box-binding protein 1.	[2]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of X-box-binding protein 1.	[2]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of X-box-binding protein 1.	[20]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the activity of X-box-binding protein 1.	[2]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of X-box-binding protein 1.	[21]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the splicing of X-box-binding protein 1.	[22]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of X-box-binding protein 1.	[23]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of X-box-binding protein 1.	[24]
Sertraline	DM0FB1J	Approved	Sertraline increases the splicing of X-box-binding protein 1.	[25]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the splicing of X-box-binding protein 1.	[26]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of X-box-binding protein 1.	[27]
Glucosamine	DM4ZLFD	Approved	Glucosamine decreases the splicing of X-box-binding protein 1.	[28]
Penicillamine	DM40EF6	Approved	Penicillamine increases the splicing of X-box-binding protein 1.	[29]
Nilotinib	DM7HXWT	Approved	Nilotinib increases the expression of X-box-binding protein 1.	[30]
Busulfan	DMXYJ9C	Approved	Busulfan affects the expression of X-box-binding protein 1.	[31]
Bupropion	DM5PCS7	Approved	Bupropion decreases the splicing of X-box-binding protein 1.	[32]
Riluzole	DMECBWN	Approved	Riluzole increases the expression of X-box-binding protein 1.	[33]
SR141716A	DMCO5JZ	Approved	SR141716A increases the expression of X-box-binding protein 1.	[34]
Pyrazinamide	DM4IF32	Approved	Pyrazinamide increases the expression of X-box-binding protein 1.	[35]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of X-box-binding protein 1.	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of X-box-binding protein 1.	[37]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the splicing of X-box-binding protein 1.	[38]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of X-box-binding protein 1.	[39]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of X-box-binding protein 1.	[40]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the splicing of X-box-binding protein 1.	[41]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of X-box-binding protein 1.	[31]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of X-box-binding protein 1.	[42]
ME-344	DM6JN19	Phase 1/2	ME-344 increases the expression of X-box-binding protein 1.	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of X-box-binding protein 1.	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of X-box-binding protein 1.	[44]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of X-box-binding protein 1.	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of X-box-binding protein 1.	[47]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of X-box-binding protein 1.	[49]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of X-box-binding protein 1.	[50]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of X-box-binding protein 1.	[51]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of X-box-binding protein 1.	[52]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of X-box-binding protein 1.	[53]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of X-box-binding protein 1.	[54]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of X-box-binding protein 1.	[55]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the splicing of X-box-binding protein 1.	[56]
D-glucose	DMMG2TO	Investigative	D-glucose increases the splicing of X-box-binding protein 1.	[57]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of X-box-binding protein 1.	[58]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the splicing of X-box-binding protein 1.	[59]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of X-box-binding protein 1.	[60]
acrolein	DMAMCSR	Investigative	acrolein affects the splicing of X-box-binding protein 1.	[61]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the splicing of X-box-binding protein 1.	[62]
AM251	DMTAWHL	Investigative	AM251 increases the expression of X-box-binding protein 1.	[63]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the splicing of X-box-binding protein 1.	[64]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide increases the expression of X-box-binding protein 1.	[65]
PATULIN	DM0RV9C	Investigative	PATULIN increases the splicing of X-box-binding protein 1.	[66]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the splicing of X-box-binding protein 1.	[67]
Aloe-emodin	DMPTY8S	Investigative	Aloe-emodin increases the splicing of X-box-binding protein 1.	[68]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of X-box-binding protein 1.	[46]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the cleavage of X-box-binding protein 1.	[48]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 2004 Jun 15;64(12):4218-26.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1. Mol Endocrinol. 2004 Feb;18(2):402-11. doi: 10.1210/me.2003-0202. Epub 2003 Nov 6.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Endoplasmic reticulum stress contributes to arsenic trioxide-induced apoptosis in drug-sensitive and -resistant leukemia cells. Leuk Res. 2012 Dec;36(12):1526-35. doi: 10.1016/j.leukres.2012.08.018. Epub 2012 Sep 7.
• [11] Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response. Am J Respir Cell Mol Biol. 2013 Dec;49(6):892-901. doi: 10.1165/rcmb.2013-0053OC.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] 9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts. Reprod Toxicol. 2019 Aug;87:21-31. doi: 10.1016/j.reprotox.2019.04.008. Epub 2019 May 1.
• [14] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Caspase-2 functions upstream of mitochondria in endoplasmic reticulum stress-induced apoptosis by bortezomib in human myeloma cells. Mol Cancer Ther. 2008 Aug;7(8):2298-307. doi: 10.1158/1535-7163.MCT-08-0186.
• [17] Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells. Antioxid Redox Signal. 2014 May 10;20(14):2091-106. doi: 10.1089/ars.2013.5240. Epub 2013 Dec 17.
• [18] Rosiglitazone induces the unfolded protein response, but has no significant effect on cell viability, in monocytic and vascular smooth muscle cells. Biochem Biophys Res Commun. 2010 Oct 1;400(4):689-95. doi: 10.1016/j.bbrc.2010.08.129. Epub 2010 Sep 9.
• [19] Anti-inflammatory agent indomethacin reduces invasion and alters metabolism in a human breast cancer cell line. Neoplasia. 2007 Mar;9(3):222-35.
• [20] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [21] Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1 and PERK pathways. Oncotarget. 2016 Jul 19;7(29):46100-46119. doi: 10.18632/oncotarget.10025.
• [22] The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress. Mol Cell Biol. 2007 Aug;27(15):5499-513. doi: 10.1128/MCB.01080-06. Epub 2007 Jun 4.
• [23] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [24] Gap junctional intercellular communication and endoplasmic reticulum stress regulate chronic cadmium exposure induced apoptosis in HK-2 cells. Toxicol Lett. 2018 May 15;288:35-43. doi: 10.1016/j.toxlet.2018.02.013. Epub 2018 Feb 11.
• [25] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [26] Endoplasmic Reticulum Stress Induction and ERK1/2 Activation Contribute to Nefazodone-Induced Toxicity in Hepatic Cells. Toxicol Sci. 2016 Dec;154(2):368-380. doi: 10.1093/toxsci/kfw173. Epub 2016 Sep 9.
• [27] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [28] Glucosamine-induced endoplasmic reticulum stress attenuates apolipoprotein B100 synthesis via PERK signaling. J Lipid Res. 2009 Sep;50(9):1814-23. doi: 10.1194/jlr.M800343-JLR200. Epub 2009 Apr 21.
• [29] N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway. Mol Carcinog. 2010 Jan;49(1):68-74. doi: 10.1002/mc.20578.
• [30] Endoplasmic reticulum stress-mediated apoptosis in imatinib-resistant leukemic K562-r cells triggered by AMN107 combined with arsenic trioxide. Exp Biol Med (Maywood). 2013 Aug 1;238(8):932-42. doi: 10.1177/1535370213492689. Epub 2013 Jul 24.
• [31] Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air-liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells. Cell Biol Toxicol. 2023 Feb;39(1):1-18. doi: 10.1007/s10565-022-09726-0. Epub 2022 May 31.
• [32] Bupropion, an atypical antidepressant, induces endoplasmic reticulum stress and caspase-dependent cytotoxicity in SH-SY5Y cells. Toxicology. 2011 Jul 11;285(1-2):1-7. doi: 10.1016/j.tox.2011.02.006. Epub 2011 Feb 24.
• [33] Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen-dependent and castration-resistant prostate cancer cells. Prostate. 2019 Feb;79(2):140-150. doi: 10.1002/pros.23719. Epub 2018 Oct 2.
• [34] Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis. 2011 Apr 28;2(4):e152. doi: 10.1038/cddis.2011.36.
• [35] Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2-ATF4-CHOP pathway. Toxicology. 2017 Mar 1;378:65-75. doi: 10.1016/j.tox.2017.01.002. Epub 2017 Jan 4.
• [36] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [37] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [38] Resveratrol induces pro-apoptotic endoplasmic reticulum stress in human colon cancer cells. Oncol Rep. 2007 Nov;18(5):1269-73.
• [39] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [40] Paraptosis in human glioblastoma cell line induced by curcumin. Toxicol In Vitro. 2018 Sep;51:63-73. doi: 10.1016/j.tiv.2018.04.014. Epub 2018 Apr 30.
• [41] Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57. Br J Cancer. 2007 Apr 10;96(7):1062-71. doi: 10.1038/sj.bjc.6603672. Epub 2007 Mar 13.
• [42] Role of endoplasmic reticulum stress in alpha-TEA mediated TRAIL/DR5 death receptor dependent apoptosis. PLoS One. 2010 Jul 29;5(7):e11865. doi: 10.1371/journal.pone.0011865.
• [43] Isoflavone ME-344 Disrupts Redox Homeostasis and Mitochondrial Function by Targeting Heme Oxygenase 1. Cancer Res. 2019 Aug 15;79(16):4072-4085. doi: 10.1158/0008-5472.CAN-18-3503. Epub 2019 Jun 21.
• [44] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [45] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [46] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [47] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [48] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [49] The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation. Am J Physiol Lung Cell Mol Physiol. 2016 Nov 1;311(5):L846-L854. doi: 10.1152/ajplung.00449.2015. Epub 2016 Sep 16.
• [50] Effects of bisphenol A on uterine leiomyoma: In vitro and in vivo evaluation with mechanistic insights related to XBP1. Ecotoxicol Environ Saf. 2022 Dec 1;247:114201. doi: 10.1016/j.ecoenv.2022.114201. Epub 2022 Oct 25.
• [51] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [52] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [53] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [54] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [55] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [56] Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces hepatic steatosis and endoplasmic reticulum stress by inducing nuclear factor erythroid-derived 2-related factor 2 nuclear translocation. Toxicol Appl Pharmacol. 2018 Dec 1;360:18-29.
• [57] HHQ-4, a quinoline derivate, preferentially inhibits proliferation of glucose-deprived breast cancer cells as a GRP78 down-regulator. Toxicol Appl Pharmacol. 2019 Jun 15;373:10-25. doi: 10.1016/j.taap.2019.04.017. Epub 2019 Apr 22.
• [58] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [59] Chlorpyrifos induces endoplasmic reticulum stress in JEG-3 cells. Toxicol In Vitro. 2017 Apr;40:88-93. doi: 10.1016/j.tiv.2016.12.008. Epub 2016 Dec 16.
• [60] Bilirubin-induced ER stress contributes to the inflammatory response and apoptosis in neuronal cells. Arch Toxicol. 2017 Apr;91(4):1847-1858. doi: 10.1007/s00204-016-1835-3. Epub 2016 Aug 30.
• [61] Role of endoplasmic reticulum stress in acrolein-induced endothelial activation. Toxicol Appl Pharmacol. 2009 Jan 1;234(1):14-24. doi: 10.1016/j.taap.2008.09.019. Epub 2008 Oct 7.
• [62] Tributyltin-induced endoplasmic reticulum stress and its Ca(2+)-mediated mechanism. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):137-46. doi: 10.1016/j.taap.2013.05.026. Epub 2013 Jun 3.
• [63] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [64] Endoplasmic Reticulum Stress and Store-Operated Calcium Entry Contribute to Usnic Acid-Induced Toxicity in Hepatic Cells. Toxicol Sci. 2015 Jul;146(1):116-26. doi: 10.1093/toxsci/kfv075. Epub 2015 Apr 13.
• [65] Association between arsenic suppression of adipogenesis and induction of CHOP10 via the endoplasmic reticulum stress response. Environ Health Perspect. 2013 Feb;121(2):237-43. doi: 10.1289/ehp.1205731. Epub 2012 Dec 5.
• [66] Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response. J Biomol Screen. 2011 Sep;16(8):825-35. doi: 10.1177/1087057111414893. Epub 2011 Aug 15.
• [67] Recruitment of endoplasmic reticulum-targeted and cytosolic mRNAs into membrane-associated stress granules. RNA. 2021 Oct;27(10):1241-1256. doi: 10.1261/rna.078858.121. Epub 2021 Jul 8.
• [68] The endoplasmic reticulum stress response is involved in apoptosis induced by aloe-emodin in HK-2 cells. Food Chem Toxicol. 2012 Mar;50(3-4):1149-58. doi: 10.1016/j.fct.2011.12.018. Epub 2011 Dec 21.
• [69] Protective effect against Parkinson's disease-related insults through the activation of XBP1. Brain Res. 2009 Feb 27;1257:16-24. doi: 10.1016/j.brainres.2008.11.104. Epub 2008 Dec 16.