Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUP3OH3)

• DOT Name: Protein orai-3 (ORAI3)
• Synonyms: Transmembrane protein 142C
• Gene Name: ORAI3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Estrogen-receptor positive breast cancer
  Immunodeficiency
  Lung adenocarcinoma
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Staphylococcus infection
  Advanced cancer
  Chronic obstructive pulmonary disease
  Digestive system neuroendocrine tumor, grade 1/2
  High blood pressure
  Neoplasm
• UniProt ID: ORAI3_HUMAN
• Pfam ID: PF07856
• Sequence:
  MKGGEGDAGEQAPLNPEGESPAGSATYREFVHRGYLDLMGASQHSLRALSWRRLYLSRAK
  LKASSRTSALLSGFAMVAMVEVQLESDHEYPPGLLVAFSACTTVLVAVHLFALMVSTCLL
  PHIEAVSNIHNLNSVHQSPHQRLHRYVELAWGFSTALGTFLFLAEVVLVGWVKFVPIGAP
  LDTPTPMVPTSRVPGTLAPVATSLSPASNLPRSSASAAPSQAEPACPPRQACGGGGAHGP
  GWQAAMASTAIMVPVGLVFVAFALHFYRSLVAHKTDRYKQELEELNRLQGELQAV
• Function: Ca(2+) release-activated Ca(2+)-like (CRAC-like) channel subunit which mediates Ca(2+) influx and increase in Ca(2+)-selective current by synergy with the Ca(2+) sensor, STIM1.
• Tissue Specificity: Expressed in both naive and effector T helper cells with higher levels in effector cells.
• KEGG Pathway: Calcium sig.ling pathway (hsa04020)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Cardiac failure	DISDC067	Strong	Posttranslational Modification	[2]
Congestive heart failure	DIS32MEA	Strong	Posttranslational Modification	[2]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[1]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Staphylococcus infection	DISY8WGS	Strong	Altered Expression	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Altered Expression	[8]
Digestive system neuroendocrine tumor, grade 1/2	DISDR98B	Limited	Biomarker	[9]
High blood pressure	DISY2OHH	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]

21 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 Protein orai-3 (ORAI3).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein orai-3 (ORAI3).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein orai-3 (ORAI3).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein orai-3 (ORAI3).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein orai-3 (ORAI3).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein orai-3 (ORAI3).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein orai-3 (ORAI3).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein orai-3 (ORAI3).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Protein orai-3 (ORAI3).	[20]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Protein orai-3 (ORAI3).	[21]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Protein orai-3 (ORAI3).	[16]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Protein orai-3 (ORAI3).	[21]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Protein orai-3 (ORAI3).	[21]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Protein orai-3 (ORAI3).	[16]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Protein orai-3 (ORAI3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein orai-3 (ORAI3).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein orai-3 (ORAI3).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein orai-3 (ORAI3).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein orai-3 (ORAI3).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein orai-3 (ORAI3).	[26]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate affects the expression of Protein orai-3 (ORAI3).	[27]

References

• [1] ORAI1 and ORAI3 in Breast Cancer Molecular Subtypes and the Identification of ORAI3 as a Hypoxia Sensitive Gene and a Regulator of Hypoxia Responses.Cancers (Basel). 2019 Feb 11;11(2):208. doi: 10.3390/cancers11020208.
• [2] Cardiac inflammatory CD11b/c cells exert a protective role in hypertrophied cardiomyocyte by promoting TNFR(2)- and Orai3- dependent signaling.Sci Rep. 2019 Apr 15;9(1):6047. doi: 10.1038/s41598-019-42452-y.
• [3] ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia.J Allergy Clin Immunol. 2009 Dec;124(6):1311-1318.e7. doi: 10.1016/j.jaci.2009.10.007.
• [4] Orai3 constitutes a native store-operated calcium entry that regulates non small cell lung adenocarcinoma cell proliferation.PLoS One. 2013 Sep 13;8(9):e72889. doi: 10.1371/journal.pone.0072889. eCollection 2013.
• [5] Overexpression of certain transient receptor potential and Orai channels in prostate cancer is associated with decreased risk of systemic recurrence after radical prostatectomy.Prostate. 2019 Dec;79(16):1793-1804. doi: 10.1002/pros.23904. Epub 2019 Sep 2.
• [6] A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels.Sci Signal. 2016 Mar 8;9(418):ra26. doi: 10.1126/scisignal.aaf1639.
• [7] Regulation of proto-oncogene Orai3 by miR18a/b and miR34a.Cell Calcium. 2018 Nov;75:101-111. doi: 10.1016/j.ceca.2018.08.006. Epub 2018 Sep 3.
• [8] Bronchial Epithelial Calcium Metabolism Impairment in Smokers and Chronic Obstructive Pulmonary Disease. Decreased ORAI3 Signaling.Am J Respir Cell Mol Biol. 2019 Oct;61(4):501-511. doi: 10.1165/rcmb.2018-0228OC.
• [9] Arachidonic acid-induced Ca(2+) entry and migration in a neuroendocrine cancer cell line.Cancer Cell Int. 2018 Mar 2;18:30. doi: 10.1186/s12935-018-0529-8. eCollection 2018.
• [10] TRPP2 associates with STIM1 to regulate cerebral vasoconstriction and enhance high salt intake-induced hypertensive cerebrovascular spasm.Hypertens Res. 2019 Dec;42(12):1894-1904. doi: 10.1038/s41440-019-0324-5. Epub 2019 Sep 20.
• [11] Differential Redox Regulation of Ca?Signaling and Viability in Normal and Malignant Prostate Cells.Biophys J. 2015 Oct 6;109(7):1410-9. doi: 10.1016/j.bpj.2015.08.006.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [23] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [24] 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.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Molecular mechanism of di-n-butyl phthalate promotion of bladder cancer development. Toxicol In Vitro. 2023 Feb;86:105508. doi: 10.1016/j.tiv.2022.105508. Epub 2022 Nov 12.