Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVFUJ13)

• DOT Name: Protein disulfide-isomerase A4 (PDIA4)
• Synonyms: EC 5.3.4.1; Endoplasmic reticulum resident protein 70; ER protein 70; ERp70; Endoplasmic reticulum resident protein 72; ER protein 72; ERp-72; ERp72
• Gene Name: PDIA4
• Related Disease:
  Advanced cancer
  Epithelial ovarian cancer
  Inflammatory bowel disease
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: PDIA4_HUMAN
• PDB ID: 3IDV
• EC Number: 5.3.4.1
• Pfam ID: PF00085 ; PF13848
• Sequence:
  MRPRKAFLLLLLLGLVQLLAVAGAEGPDEDSSNRENAIEDEEEEEEEDDDEEEDDLEVKE
  ENGVLVLNDANFDNFVADKDTVLLEFYAPWCGHCKQFAPEYEKIANILKDKDPPIPVAKI
  DATSASVLASRFDVSGYPTIKILKKGQAVDYEGSRTQEEIVAKVREVSQPDWTPPPEVTL
  VLTKENFDEVVNDADIILVEFYAPWCGHCKKLAPEYEKAAKELSKRSPPIPLAKVDATAE
  TDLAKRFDVSGYPTLKIFRKGRPYDYNGPREKYGIVDYMIEQSGPPSKEILTLKQVQEFL
  KDGDDVIIIGVFKGESDPAYQQYQDAANNLREDYKFHHTFSTEIAKFLKVSQGQLVVMQP
  EKFQSKYEPRSHMMDVQGSTQDSAIKDFVLKYALPLVGHRKVSNDAKRYTRRPLVVVYYS
  VDFSFDYRAATQFWRSKVLEVAKDFPEYTFAIADEEDYAGEVKDLGLSESGEDVNAAILD
  ESGKKFAMEPEEFDSDTLREFVTAFKKGKLKPVIKSQPVPKNNKGPVKVVVGKTFDSIVM
  DPKKDVLIEFYAPWCGHCKQLEPVYNSLAKKYKGQKGLVIAKMDATANDVPSDRYKVEGF
  PTIYFAPSGDKKNPVKFEGGDRDLEHLSKFIEEHATKLSRTKEEL
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Thyroid hormone synthesis (hsa04918)
  Vibrio cholerae infection (hsa05110)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein disulfide-isomerase A4 (PDIA4).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein disulfide-isomerase A4 (PDIA4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein disulfide-isomerase A4 (PDIA4).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Protein disulfide-isomerase A4 (PDIA4).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein disulfide-isomerase A4 (PDIA4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein disulfide-isomerase A4 (PDIA4).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein disulfide-isomerase A4 (PDIA4).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Protein disulfide-isomerase A4 (PDIA4).	[20]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Protein disulfide-isomerase A4 (PDIA4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Protein disulfide-isomerase A4 (PDIA4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein disulfide-isomerase A4 (PDIA4).	[16]

References

• [1] PDIA4: The basic characteristics, functions and its potential connection with cancer.Biomed Pharmacother. 2020 Feb;122:109688. doi: 10.1016/j.biopha.2019.109688. Epub 2019 Nov 30.
• [2] Microarray-based identification of genes associated with prognosis and drug resistance in ovarian cancer.J Cell Biochem. 2019 Apr;120(4):6057-6070. doi: 10.1002/jcb.27892. Epub 2018 Oct 18.
• [3] Involvement of endoplasmic reticulum stress in inflammatory bowel disease: a different implication for colonic and ileal disease?.PLoS One. 2011;6(10):e25589. doi: 10.1371/journal.pone.0025589. Epub 2011 Oct 18.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Toxicogenomics-based discrimination of toxic mechanism in HepG2 human hepatoma cells. Toxicol Sci. 2000 Dec;58(2):399-415.
• [9] 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.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] 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.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [21] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.