Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2GBV06)

• DOT Name: Prostaglandin E2 receptor EP4 subtype (PTGER4)
• Synonyms: PGE receptor EP4 subtype; PGE2 receptor EP4 subtype; Prostanoid EP4 receptor
• Gene Name: PTGER4
• UniProt ID: PE2R4_HUMAN
• PDB ID: 5YHL; 5YWY; 7D7M
• Pfam ID: PF00001
• Sequence:
  MSTPGVNSSASLSPDRLNSPVTIPAVMFIFGVVGNLVAIVVLCKSRKEQKETTFYTLVCG
  LAVTDLLGTLLVSPVTIATYMKGQWPGGQPLCEYSTFILLFFSLSGLSIICAMSVERYLA
  INHAYFYSHYVDKRLAGLTLFAVYASNVLFCALPNMGLGSSRLQYPDTWCFIDWTTNVTA
  HAAYSYMYAGFSSFLILATVLCNVLVCGALLRMHRQFMRRTSLGTEQHHAAAAASVASRG
  HPAASPALPRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLVVRVFVNQLYQP
  SLEREVSKNPDLQAIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSRRERSG
  QHCSDSQRTSSAMSGHSRSFISRELKEISSTSQTLLPDLSLPDLSENGLGGRNLLPGVPG
  MGLAQEDTTSLRTLRISETSDSSQGQDSESVLLVDEAGGSGRAGPAPKGSSLQVTFPSET
  LNLSEKCI
• Function: Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function.
• Tissue Specificity: High in intestine and in peripheral blood mononuclear cells; low in lung, kidney, thymus, uterus, vasculature and brain. Not found in liver, heart, retina oe skeletal muscle.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Efferocytosis (hsa04148)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Renin secretion (hsa04924)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Prostanoid ligand receptors (R-HSA-391908)

Molecular Interaction Atlas (MIA) of This DOT

26 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 Prostaglandin E2 receptor EP4 subtype (PTGER4).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[13]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[14]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[15]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the activity of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[14]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[23]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[24]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Prostaglandin E2 receptor EP4 subtype (PTGER4).	[25]

References

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• [2] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [3] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] 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.
• [15] 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.
• [16] Role of hypoxia-inducible factor 1, subunit and cAMP-response element binding protein 1 in synergistic release of interleukin 8 by prostaglandin E2 and nickel in lung fibroblasts. Am J Respir Cell Mol Biol. 2013 Jul;49(1):105-13. doi: 10.1165/rcmb.2012-0297OC.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009 Mar 4;28(5):523-32.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] 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.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [23] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [24] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [25] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.