Details of Drug Off-Target (DOT)

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

• DOT Name: Neuroepithelial cell-transforming gene 1 protein (NET1)
• Synonyms: Proto-oncogene p65 Net1; Rho guanine nucleotide exchange factor 8
• Gene Name: NET1
• Related Disease:
  Advanced cancer
  Subarachnoid hemorrhage
  Acute lymphocytic leukaemia
  Adenocarcinoma
  Attention deficit hyperactivity disorder
  Barrett esophagus
  Breast cancer
  Breast neoplasm
  Carcinoma
  Cervical Intraepithelial neoplasia
  Childhood acute lymphoblastic leukemia
  Dentin dysplasia
  Dentinogenesis imperfecta
  Esophageal cancer
  Gastric adenocarcinoma
  Hepatocellular carcinoma
  Herpes simplex infection
  Non-small-cell lung cancer
  Bladder cancer
  Cutaneous squamous cell carcinoma
  Gastric cancer
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast carcinoma
• UniProt ID: ARHG8_HUMAN
• PDB ID: 3EO2; 4XH9
• Pfam ID: PF00169 ; PF00621
• Sequence:
  MEPELAAQKQPRPRRRSRRASGLSTEGATGPSADTSGSELDGRCSLRRGSSFTFLTPGPN
  WDFTLKRKRREKDDDVVSLSSLDLKEPSNKRVRPLARVTSLANLISPVRNGAVRRFGQTI
  QSFTLRGDHRSPASAQKFSSRSTVPTPAKRRSSALWSEMLDITMKESLTTREIRRQEAIY
  EMSRGEQDLIEDLKLARKAYHDPMLKLSIMSEEELTHIFGDLDSYIPLHEDLLTRIGEAT
  KPDGTVEQIGHILVSWLPRLNAYRGYCSNQLAAKALLDQKKQDPRVQDFLQRCLESPFSR
  KLDLWSFLDIPRSRLVKYPLLLKEILKHTPKEHPDVQLLEDAILIIQGVLSDINLKKGES
  ECQYYIDKLEYLDEKQRDPRIEASKVLLCHGELRSKSGHKLYIFLFQDILVLTRPVTRNE
  RHSYQVYRQPIPVQELVLEDLQDGDVRMGGSFRGAFSNSEKAKNIFRIRFHDPSPAQSHT
  LQANDVFHKQQWFNCIRAAIAPFQSAGSPPELQGLPELHEECEGNHPSARKLTAQRRAST
  VSSVTQVEVDENAYRCGSGMQMAEDSKSLKTHQTQPGIRRARDKALSGGKRKETLV
• Function: Acts as a guanine nucleotide exchange factor (GEF) for RhoA GTPase. May be involved in activation of the SAPK/JNK pathway Stimulates genotoxic stress-induced RHOB activity in breast cancer cells leading to their cell death.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Subarachnoid hemorrhage	DISI7I8Y	Definitive	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[4]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Altered Expression	[8]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[1]
Dentin dysplasia	DISCGIX8	Strong	Genetic Variation	[9]
Dentinogenesis imperfecta	DISJLZU4	Strong	Genetic Variation	[9]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[5]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Bladder cancer	DISUHNM0	moderate	Biomarker	[13]
Cutaneous squamous cell carcinoma	DIS3LXUG	moderate	Biomarker	[14]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[15]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[15]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[13]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[13]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Neuroepithelial cell-transforming gene 1 protein (NET1).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Neuroepithelial cell-transforming gene 1 protein (NET1).	[32]

19 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 Neuroepithelial cell-transforming gene 1 protein (NET1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[24]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[25]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[26]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[27]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[28]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[34]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Neuroepithelial cell-transforming gene 1 protein (NET1).	[35]

References

• [1] NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells.Oncol Res. 2019 Aug 8;27(8):935-944. doi: 10.3727/096504019X15555388198071. Epub 2019 Apr 17.
• [2] Endovascular Therapy for Ruptured Vertebral Artery Dissecting Aneurysms: Results from Nationwide, Retrospective, Multi-Center Registries in Japan (JR-NET3).Neurol Med Chir (Tokyo). 2019 Jan 15;59(1):10-18. doi: 10.2176/nmc.st.2018-0191. Epub 2018 Dec 7.
• [3] Prognostic significance of neuroepithelial transforming gene 1 in adenocarcinoma of the oesophagogastric junction.Br J Surg. 2014 Jan;101(2):55-62. doi: 10.1002/bjs.9373.
• [4] The relationship between the presence of ADHD and certain candidate gene polymorphisms in a Turkish sample.Gene. 2013 Oct 10;528(2):320-7. doi: 10.1016/j.gene.2013.07.004. Epub 2013 Jul 18.
• [5] Expression of neuroepithelial transforming gene 1 is enhanced in oesophageal cancer and mediates an invasive tumour cell phenotype.J Exp Clin Cancer Res. 2013 Aug 14;32(1):55. doi: 10.1186/1756-9966-32-55.
• [6] Contributions of the RhoA guanine nucleotide exchange factor Net1 to polyoma middle T antigen-mediated mammary gland tumorigenesis and metastasis.Breast Cancer Res. 2018 May 16;20(1):41. doi: 10.1186/s13058-018-0966-2.
• [7] Coexpression of alpha6beta4 integrin and guanine nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis.Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):80-6. doi: 10.1158/1055-9965.EPI-08-0842.
• [8] Identification of a new proliferation-associated protein NET-1/C4.8 characteristic for a subset of high-grade cervical intraepithelial neoplasia and cervical carcinomas.Int J Cancer. 2002 Jun 20;99(6):771-5. doi: 10.1002/ijc.10442.
• [9] Overlapping DSPP mutations cause dentin dysplasia and dentinogenesis imperfecta.J Dent Res. 2008 Dec;87(12):1108-11. doi: 10.1177/154405910808701217.
• [10] Inhibition of NET-1 suppresses proliferation and promotes apoptosis of hepatocellular carcinoma cells by activating the PI3K/AKT signaling pathway.Exp Ther Med. 2019 Mar;17(3):2334-2340. doi: 10.3892/etm.2019.7211. Epub 2019 Jan 29.
• [11] A net +1 frameshift permits synthesis of thymidine kinase from a drug-resistant herpes simplex virus mutant.Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5461-5. doi: 10.1073/pnas.91.12.5461.
• [12] Neuroepithelial transforming gene 1 functions as a potential prognostic marker for patients with non-small cell lung cancer.Mol Med Rep. 2015 Nov;12(5):7439-46. doi: 10.3892/mmr.2015.4385. Epub 2015 Sep 29.
• [13] miR?2?p enhances multichemoresistance by targeting NET1 in bladder cancer cells.Oncol Rep. 2018 Jun;39(6):2731-2740. doi: 10.3892/or.2018.6355. Epub 2018 Apr 4.
• [14] Inhibition of skin squamous cell carcinoma proliferation and promote apoptosis by dual silencing of NET-1 and survivin.Oncol Rep. 2015 Aug;34(2):811-22. doi: 10.3892/or.2015.4062. Epub 2015 Jun 15.
• [15] LncRNA CTC-497E21.4 promotes the progression of gastric cancer via modulating miR-22/NET1 axis through RhoA signaling pathway.Gastric Cancer. 2020 Mar;23(2):228-240. doi: 10.1007/s10120-019-00998-w. Epub 2019 Aug 26.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [24] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [25] 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.
• [26] 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.
• [27] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [28] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [29] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [30] 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.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [33] 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.
• [34] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [35] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.