Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8YBR17)

• DOT Name: Protein disulfide-isomerase A6 (PDIA6)
• Synonyms: EC 5.3.4.1; Endoplasmic reticulum protein 5; ER protein 5; ERp5; Protein disulfide isomerase P5; Thioredoxin domain-containing protein 7
• Gene Name: PDIA6
• Related Disease:
  Acute myocardial infarction
  Alzheimer disease
  Bladder cancer
  Bone giant cell tumor
  Breast cancer
  Breast carcinoma
  Classic Hodgkin lymphoma
  Ductal carcinoma
  Huntington disease
  Lung squamous cell carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: PDIA6_HUMAN
• PDB ID: 1X5D; 3VWW; 3W8J; 4EF0; 4GWR
• EC Number: 5.3.4.1
• Pfam ID: PF00085
• Sequence:
  MALLVLGLVSCTFFLAVNGLYSSSDDVIELTPSNFNREVIQSDSLWLVEFYAPWCGHCQR
  LTPEWKKAATALKDVVKVGAVDADKHHSLGGQYGVQGFPTIKIFGSNKNRPEDYQGGRTG
  EAIVDAALSALRQLVKDRLGGRSGGYSSGKQGRSDSSSKKDVIELTDDSFDKNVLDSEDV
  WMVEFYAPWCGHCKNLEPEWAAAASEVKEQTKGKVKLAAVDATVNQVLASRYGIRGFPTI
  KIFQKGESPVDYDGGRTRSDIVSRALDLFSDNAPPPELLEIINEDIAKRTCEEHQLCVVA
  VLPHILDTGAAGRNSYLEVLLKLADKYKKKMWGWLWTEAGAQSELETALGIGGFGYPAMA
  AINARKMKFALLKGSFSEQGINEFLRELSFGRGSTAPVGGGAFPTIVEREPWDGRDGELP
  VEDDIDLSDVELDDLGKDEL
• Function: May function as a chaperone that inhibits aggregation of misfolded proteins. Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling. May also regulate the UPR via the EIF2AK3 UPR sensor. Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin.
• Tissue Specificity: Expressed in platelets (at protein level).
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Bone giant cell tumor	DIS0RGK9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[6]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[8]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein disulfide-isomerase A6 (PDIA6).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein disulfide-isomerase A6 (PDIA6).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein disulfide-isomerase A6 (PDIA6).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein disulfide-isomerase A6 (PDIA6).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein disulfide-isomerase A6 (PDIA6).	[16]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein disulfide-isomerase A6 (PDIA6).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[23]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Protein disulfide-isomerase A6 (PDIA6).	[24]

References

• [1] Hypoxia evokes increased PDI and PDIA6 expression in the infarcted myocardium of ex-germ-free and conventionally raised mice.Biol Open. 2019 Jan 2;8(1):bio038851. doi: 10.1242/bio.038851.
• [2] Decreased levels of PDI and P5 in oligodendrocytes in Alzheimer's disease.Neuropathology. 2017 Dec;37(6):495-501. doi: 10.1111/neup.12395. Epub 2017 Jul 21.
• [3] The Inhibitory Effect of PDIA6 Downregulation on Bladder Cancer Cell Proliferation and Invasion.Oncol Res. 2017 Apr 14;25(4):587-593. doi: 10.3727/096504016X14761811155298. Epub 2016 Oct 18.
• [4] MiR-127 and miR-376a act as tumor suppressors by invivo targeting of COA1 and PDIA6 in giant cell tumor of bone.Cancer Lett. 2017 Nov 28;409:49-55. doi: 10.1016/j.canlet.2017.08.029. Epub 2017 Sep 1.
• [5] In vivo selection for metastasis promoting genes in the mouse.Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6696-701. doi: 10.1073/pnas.0701145104. Epub 2007 Apr 9.
• [6] High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas.Blood. 2012 Feb 9;119(6):1479-89. doi: 10.1182/blood-2011-07-370841. Epub 2011 Dec 13.
• [7] PDIA3 and PDIA6 gene expression as an aggressiveness marker in primary ductal breast cancer.Genet Mol Res. 2015 Jun 26;14(2):6960-7. doi: 10.4238/2015.June.26.4.
• [8] Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains.Hum Mol Genet. 2015 Mar 1;24(5):1441-56. doi: 10.1093/hmg/ddu561. Epub 2014 Dec 5.
• [9] PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway.EBioMedicine. 2019 Apr;42:311-325. doi: 10.1016/j.ebiom.2019.03.045. Epub 2019 Mar 25.
• [10] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [11] PDIA6 regulation of ADAM17 shedding activity and EGFR-mediated migration and invasion of glioblastoma cells.J Neurosurg. 2017 Jun;126(6):1829-1838. doi: 10.3171/2016.5.JNS152831. Epub 2016 Aug 19.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [19] 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.
• [20] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.