Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUK0TDC)

• DOT Name: G-protein coupled estrogen receptor 1 (GPER1)
• Synonyms: Chemoattractant receptor-like 2; Flow-induced endothelial G-protein coupled receptor 1; FEG-1; G protein-coupled estrogen receptor 1; G-protein coupled receptor 30; GPCR-Br; IL8-related receptor DRY12; Lymphocyte-derived G-protein coupled receptor; LYGPR; Membrane estrogen receptor; mER
• Gene Name: GPER1
• UniProt ID: GPER1_HUMAN
• Pfam ID: PF00001
• Sequence:
  MDVTSQARGVGLEMYPGTAQPAAPNTTSPELNLSHPLLGTALANGTGELSEHQQYVIGLF
  LSCLYTIFLFPIGFVGNILILVVNISFREKMTIPDLYFINLAVADLILVADSLIEVFNLH
  ERYYDIAVLCTFMSLFLQVNMYSSVFFLTWMSFDRYIALARAMRCSLFRTKHHARLSCGL
  IWMASVSATLVPFTAVHLQHTDEACFCFADVREVQWLEVTLGFIVPFAIIGLCYSLIVRV
  LVRAHRHRGLRPRRQKALRMILAVVLVFFVCWLPENVFISVHLLQRTQPGAAPCKQSFRH
  AHPLTGHIVNLAAFSNSCLNPLIYSFLGETFRDKLRLYIEQKTNLPALNRFCHAALKAVI
  PDSTEQSDVRFSSAV
• Function: G-protein coupled estrogen receptor that binds to 17-beta-estradiol (E2) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Stimulates cAMP production, calcium mobilization and tyrosine kinase Src inducing the release of heparin-bound epidermal growth factor (HB-EGF) and subsequent transactivation of the epidermal growth factor receptor (EGFR), activating downstream signaling pathways such as PI3K/Akt and ERK/MAPK. Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. Has a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a RAMP3-dependent manner. Regulates arterial blood pressure by stimulating vasodilation and reducing vascular smooth muscle and microvascular endothelial cell proliferation. Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. Stimulates uterine epithelial cell proliferation. Enhances uterine contractility in response to oxytocin. Contributes to thymic atrophy by inducing apoptosis. Attenuates TNF-mediated endothelial expression of leukocyte adhesion molecules. Promotes neuritogenesis in developing hippocampal neurons. Plays a role in acute neuroprotection against NMDA-induced excitotoxic neuronal death. Increases firing activity and intracellular calcium oscillations in luteinizing hormone-releasing hormone (LHRH) neurons. Inhibits early osteoblast proliferation at growth plate during skeletal development. Inhibits mature adipocyte differentiation and lipid accumulation. Involved in the recruitment of beta-arrestin 2 ARRB2 at the plasma membrane in epithelial cells. Functions also as a receptor for aldosterone mediating rapid regulation of vascular contractibility through the PI3K/ERK signaling pathway. Involved in cancer progression regulation. Stimulates cancer-associated fibroblast (CAF) proliferation by a rapid genomic response through the EGFR/ERK transduction pathway. Associated with EGFR, may act as a transcription factor activating growth regulatory genes (c-fos, cyclin D1). Promotes integrin alpha-5/beta-1 and fibronectin (FN) matrix assembly in breast cancer cells.
• Tissue Specificity: Expressed in placenta, endothelial and epithelial cells, non laboring and laboring term myometrium, fibroblasts and cancer-associated fibroblasts (CAF), prostate cancer cells and invasive adenocarcinoma (at protein level). Ubiquitously expressed, but is most abundant in placenta. In brain regions, expressed as a 2.8 kb transcript in basal forebrain, frontal cortex, thalamus, hippocampus, caudate and putamen.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Estrogen sig.ling pathway (hsa04915)
  GnRH secretion (hsa04929)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  GPER1 signaling (R-HSA-9634597)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

2 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 G-protein coupled estrogen receptor 1 (GPER1).	[1]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the methylation of G-protein coupled estrogen receptor 1 (GPER1).	[6]

27 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 G-protein coupled estrogen receptor 1 (GPER1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of G-protein coupled estrogen receptor 1 (GPER1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of G-protein coupled estrogen receptor 1 (GPER1).	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[15]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[13]
Prasterone	DM67VKL	Approved	Prasterone increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[16]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[17]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the activity of G-protein coupled estrogen receptor 1 (GPER1).	[18]
Puerarin	DMJIMXH	Phase 2	Puerarin increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[22]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[10]
N-nonylphenol	DMH3OUX	Investigative	N-nonylphenol increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[13]
Tetramethylbutylphenol	DMW9CH2	Investigative	Tetramethylbutylphenol increases the expression of G-protein coupled estrogen receptor 1 (GPER1).	[13]

References

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• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] 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.
• [8] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [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] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [11] 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.
• [12] Dehydroepiandrosterone Activation of G-protein-coupled Estrogen Receptor Rapidly Stimulates MicroRNA-21 Transcription in Human Hepatocellular Carcinoma Cells. J Biol Chem. 2015 Jun 19;290(25):15799-15811. doi: 10.1074/jbc.M115.641167. Epub 2015 May 11.
• [13] Prediction of the combined effects of multiple estrogenic chemicals on MCF-7 human breast cancer cells and a preliminary molecular exploration of the estrogenic proliferative effects and related gene expression. Ecotoxicol Environ Saf. 2018 Sep 30;160:1-9. doi: 10.1016/j.ecoenv.2018.05.025. Epub 2018 May 21.
• [14] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [18] Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009 Mar 4;28(5):523-32.
• [19] GPR30 Activation Contributes to the Puerarin-Mediated Neuroprotection in MPP(+)-Induced SH-SY5Y Cell Death. J Mol Neurosci. 2017 Feb;61(2):227-234. doi: 10.1007/s12031-016-0856-y. Epub 2016 Oct 30.
• [20] 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.
• [21] Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders. J Mol Endocrinol. 2015 Jun;54(3):289-303.
• [22] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [23] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.