Details of Drug Off-Target (DOT)

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

• DOT Name: ERO1-like protein alpha (ERO1A)
• Synonyms: ERO1-L; ERO1-L-alpha; EC 1.8.4.-; Endoplasmic oxidoreductin-1-like protein; Endoplasmic reticulum oxidoreductase alpha; Oxidoreductin-1-L-alpha
• Gene Name: ERO1A
• Related Disease:
  Acute liver failure
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Cholangiocarcinoma
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Immunodeficiency
  Non-small-cell lung cancer
  Gastric cancer
  Hypoglycemia
  Plasma cell myeloma
  Stomach cancer
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Pancreatic cancer
  Triple negative breast cancer
• UniProt ID: ERO1A_HUMAN
• PDB ID: 3AHQ; 3AHR
• EC Number: 1.8.4.-
• Pfam ID: PF04137
• Sequence:
  MGRGWGFLFGLLGAVWLLSSGHGEEQPPETAAQRCFCQVSGYLDDCTCDVETIDRFNNYR
  LFPRLQKLLESDYFRYYKVNLKRPCPFWNDISQCGRRDCAVKPCQSDEVPDGIKSASYKY
  SEEANNLIEECEQAERLGAVDESLSEETQKAVLQWTKHDDSSDNFCEADDIQSPEAEYVD
  LLLNPERYTGYKGPDAWKIWNVIYEENCFKPQTIKRPLNPLASGQGTSEENTFYSWLEGL
  CVEKRAFYRLISGLHASINVHLSARYLLQETWLEKKWGHNITEFQQRFDGILTEGEGPRR
  LKNLYFLYLIELRALSKVLPFFERPDFQLFTGNKIQDEENKMLLLEILHEIKSFPLHFDE
  NSFFAGDKKEAHKLKEDFRLHFRNISRIMDCVGCFKCRLWGKLQTQGLGTALKILFSEKL
  IANMPESGPSYEFHLTRQEIVSLFNAFGRISTSVKELENFRNLLQNIH
• Function: Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. Required for the proper folding of immunoglobulins. Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1. Involved in the release of the unfolded cholera toxin from reduced P4HB/PDI in case of infection by V.cholerae, thereby playing a role in retrotranslocation of the toxin.
• Tissue Specificity: Widely expressed at low level. Expressed at high level in upper digestive tract. Highly expressed in esophagus. Weakly expressed in stomach and duodenum.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Vibrio cholerae infection (hsa05110)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway: Detoxification of Reactive Oxygen Species (R-HSA-3299685)
• BioCyc Pathway: MetaCyc:MONOMER66-43439

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute liver failure	DIS5EZKX	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[2]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[4]
Immunodeficiency	DIS093I0	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[8]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[9]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[10]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[12]
Pancreatic cancer	DISJC981	Limited	Biomarker	[13]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of ERO1-like protein alpha (ERO1A).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ERO1-like protein alpha (ERO1A).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ERO1-like protein alpha (ERO1A).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ERO1-like protein alpha (ERO1A).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ERO1-like protein alpha (ERO1A).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ERO1-like protein alpha (ERO1A).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of ERO1-like protein alpha (ERO1A).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of ERO1-like protein alpha (ERO1A).	[21]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ERO1-like protein alpha (ERO1A).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of ERO1-like protein alpha (ERO1A).	[22]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of ERO1-like protein alpha (ERO1A).	[23]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of ERO1-like protein alpha (ERO1A).	[23]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of ERO1-like protein alpha (ERO1A).	[23]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ERO1-like protein alpha (ERO1A).	[24]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of ERO1-like protein alpha (ERO1A).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ERO1-like protein alpha (ERO1A).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ERO1-like protein alpha (ERO1A).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ERO1-like protein alpha (ERO1A).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ERO1-like protein alpha (ERO1A).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ERO1-like protein alpha (ERO1A).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ERO1-like protein alpha (ERO1A).	[31]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of ERO1-like protein alpha (ERO1A).	[32]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of ERO1-like protein alpha (ERO1A).	[33]
NMS-873	DMYKZ6U	Investigative	NMS-873 increases the expression of ERO1-like protein alpha (ERO1A).	[34]

References

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• [2] Targeting the functional interplay between endoplasmic reticulum oxidoreductin-1 and protein disulfide isomerase suppresses the progression of cervical cancer.EBioMedicine. 2019 Mar;41:408-419. doi: 10.1016/j.ebiom.2019.02.041. Epub 2019 Feb 27.
• [3] Cancer-associated oxidoreductase ERO1- promotes immune escape through up-regulation of PD-L1 in human breast cancer.Oncotarget. 2017 Apr 11;8(15):24706-24718. doi: 10.18632/oncotarget.14960.
• [4] Expression of endoplasmic reticulum oxidoreductase 1- in cholangiocarcinoma tissues and its effects on the proliferation and migration of cholangiocarcinoma cells.Cancer Manag Res. 2019 Jul 19;11:6727-6739. doi: 10.2147/CMAR.S188746. eCollection 2019.
• [5] Hypoxia-inducible ERO1 promotes cancer progression through modulation of integrin-1 modification and signalling in HCT116 colorectal cancer cells.Sci Rep. 2017 Aug 24;7(1):9389. doi: 10.1038/s41598-017-09976-7.
• [6] Cancer-associated oxidoreductase ERO1- drives the production of VEGF via oxidative protein folding and regulating the mRNA level.Br J Cancer. 2016 May 24;114(11):1227-34. doi: 10.1038/bjc.2016.105. Epub 2016 Apr 21.
• [7] Combined expression of protein disulfide isomerase and endoplasmic reticulum oxidoreductin 1- is a poor prognostic marker for non-small cell lung cancer.Oncol Lett. 2018 Nov;16(5):5753-5760. doi: 10.3892/ol.2018.9339. Epub 2018 Aug 21.
• [8] Expression of ERO1L in gastric cancer and its association with patient prognosis.Exp Ther Med. 2017 Sep;14(3):2298-2302. doi: 10.3892/etm.2017.4782. Epub 2017 Jul 11.
• [9] Ero1-L alpha plays a key role in a HIF-1-mediated pathway to improve disulfide bond formation and VEGF secretion under hypoxia: implication for cancer.Oncogene. 2005 Feb 3;24(6):1011-20. doi: 10.1038/sj.onc.1208325.
• [10] Inhibition of the FAD containing ER oxidoreductin 1 (Ero1) protein by EN-460 as a strategy for treatment of multiple myeloma.Bioorg Med Chem. 2019 Apr 15;27(8):1479-1488. doi: 10.1016/j.bmc.2019.02.016. Epub 2019 Feb 10.
• [11] Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway.Cell Death Dis. 2018 Oct 30;9(11):1105. doi: 10.1038/s41419-018-1134-4.
• [12] Endoplasmic reticulum oxidoreductin-1 (Ero1) improves folding and secretion of mutant proinsulin and limits mutant proinsulin-induced endoplasmic reticulum stress.J Biol Chem. 2013 Oct 25;288(43):31010-8. doi: 10.1074/jbc.M113.510065. Epub 2013 Sep 10.
• [13] ERO1 promotes hypoxic tumor progression and is associated with poor prognosis in pancreatic cancer.Oncotarget. 2019 Oct 15;10(57):5970-5982. doi: 10.18632/oncotarget.27235. eCollection 2019 Oct 15.
• [14] 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.
• [15] Proteomics investigations of drug-induced hepatotoxicity in HepG2 cells. Toxicol Sci. 2011 Mar;120(1):109-22.
• [16] 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.
• [17] 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.
• [18] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] 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.
• [21] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [22] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [23] 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.
• [24] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [25] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [26] 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.
• [27] Inhibition of activity/expression, or genetic deletion, of ERO1 blunts arsenite geno- and cyto-toxicity. Food Chem Toxicol. 2022 Oct;168:113360. doi: 10.1016/j.fct.2022.113360. Epub 2022 Aug 12.
• [28] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] 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.
• [33] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [34] Interleukin-6 induced overexpression of valosin-containing protein (VCP)/p97 is associated with androgen-independent prostate cancer (AIPC) progression. J Cell Physiol. 2018 Oct;233(10):7148-7164. doi: 10.1002/jcp.26639. Epub 2018 Apr 25.