Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDRRMP3)

• DOT Name: Netrin-4 (NTN4)
• Synonyms: Beta-netrin; Hepar-derived netrin-like protein
• Gene Name: NTN4
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Colorectal carcinoma
  Corneal neovascularization
  Glioblastoma multiforme
  IgA nephropathy
  Metastatic malignant neoplasm
  Neoplasm
  Neuroblastoma
  Tourette syndrome
  Melanoma
• UniProt ID: NET4_HUMAN
• Pfam ID: PF00053 ; PF00055 ; PF01759
• Sequence:
  MGSCARLLLLWGCTVVAAGLSGVAGVSSRCEKACNPRMGNLALGRKLWADTTCGQNATEL
  YCFYSENTDLTCRQPKCDKCNAAYPHLAHLPSAMADSSFRFPRTWWQSAEDVHREKIQLD
  LEAEFYFTHLIVMFKSPRPAAMVLDRSQDFGKTWKPYKYFATNCSATFGLEDDVVKKGAI
  CTSKYSSPFPCTGGEVIFKALSPPYDTENPYSAKVQEQLKITNLRVQLLKRQSCPCQRND
  LNEEPQHFTHYAIYDFIVKGSCFCNGHADQCIPVHGFRPVKAPGTFHMVHGKCMCKHNTA
  GSHCQHCAPLYNDRPWEAADGKTGAPNECRTCKCNGHADTCHFDVNVWEASGNRSGGVCD
  DCQHNTEGQYCQRCKPGFYRDLRRPFSAPDACKPCSCHPVGSAVLPANSVTFCDPSNGDC
  PCKPGVAGRRCDRCMVGYWGFGDYGCRPCDCAGSCDPITGDCISSHTDIDWYHEVPDFRP
  VHNKSEPAWEWEDAQGFSALLHSGKCECKEQTLGNAKAFCGMKYSYVLKIKILSAHDKGT
  HVEVNVKIKKVLKSTKLKIFRGKRTLYPESWTDRGCTCPILNPGLEYLVAGHEDIRTGKL
  IVNMKSFVQHWKPSLGRKVMDILKRECK
• Function: May play an important role in neural, kidney and vascular development. Promotes neurite elongation from olfactory bulb explants.
• Tissue Specificity: Expressed in kidney, spleen, mammary gland, aorta, heart, ovary, prostate and fetal spleen.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Netrin-1 signaling (R-HSA-373752)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Corneal neovascularization	DISKOGZP	Strong	Altered Expression	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[11]
Tourette syndrome	DISX9D54	Strong	Biomarker	[12]
Melanoma	DIS1RRCY	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Netrin-4 (NTN4).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Netrin-4 (NTN4).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Netrin-4 (NTN4).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Netrin-4 (NTN4).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Netrin-4 (NTN4).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Netrin-4 (NTN4).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Netrin-4 (NTN4).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Netrin-4 (NTN4).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Netrin-4 (NTN4).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Netrin-4 (NTN4).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Netrin-4 (NTN4).	[24]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Netrin-4 (NTN4).	[25]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Netrin-4 (NTN4).	[26]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Netrin-4 (NTN4).	[27]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Netrin-4 (NTN4).	[28]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Netrin-4 (NTN4).	[29]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Netrin-4 (NTN4).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Netrin-4 (NTN4).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Netrin-4 (NTN4).	[31]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Netrin-4 (NTN4).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Netrin-4 (NTN4).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Netrin-4 (NTN4).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Netrin-4 (NTN4).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Netrin-4 (NTN4).	[36]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Netrin-4 (NTN4).	[37]

References

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• [2] NTN4 is associated with breast cancer metastasis via regulation of EMT-related biomarkers.Oncol Rep. 2017 Jan;37(1):449-457. doi: 10.3892/or.2016.5239. Epub 2016 Nov 9.
• [3] Family-based genome scan for age at onset of late-onset Alzheimer's disease in whole exome sequencing data.Genes Brain Behav. 2015 Nov;14(8):607-17. doi: 10.1111/gbb.12250. Epub 2015 Sep 23.
• [4] Tumor expression of environmental chemical-responsive genes and breast cancer mortality.Endocr Relat Cancer. 2019 Dec;26(12):843-851. doi: 10.1530/ERC-19-0357.
• [5] Netrin-4 induces lymphangiogenesis in vivo.Blood. 2010 Jul 1;115(26):5418-26. doi: 10.1182/blood-2009-11-252338. Epub 2010 Apr 20.
• [6] Netrin-4 is upregulated in breast carcinoma effusions compared to corresponding solid tumors.Diagn Cytopathol. 2011 Aug;39(8):562-6. doi: 10.1002/dc.21424. Epub 2010 Aug 20.
• [7] Netrin-4 overexpression suppresses primary and metastatic colorectal tumor progression.Oncol Rep. 2013 Jan;29(1):73-8. doi: 10.3892/or.2012.2104. Epub 2012 Oct 23.
• [8] Netrin-4 Mediates Corneal Hemangiogenesis but Not Lymphangiogenesis in the Mouse-Model of Suture-Induced Neovascularization.Invest Ophthalmol Vis Sci. 2017 Mar 1;58(3):1387-1396. doi: 10.1167/iovs.16-19249.
• [9] 3'UTR variants of TNS3, PHLDB1, NTN4, and GNG2 genes are associated with IgA nephropathy risk in Chinese Han population.Int Immunopharmacol. 2019 Jun;71:295-300. doi: 10.1016/j.intimp.2019.03.041. Epub 2019 Mar 28.
• [10] The Netrin-4/ Neogenin-1 axis promotes neuroblastoma cell survival and migration.Oncotarget. 2017 Feb 7;8(6):9767-9782. doi: 10.18632/oncotarget.14213.
• [11] The Netrin-4/Laminin 1/Neogenin-1 complex mediates migration in SK-N-SH neuroblastoma cells.Cell Adh Migr. 2019 Dec;13(1):33-40. doi: 10.1080/19336918.2018.1506652. Epub 2018 Aug 30.
• [12] Genetic association signal near NTN4 in Tourette syndrome.Ann Neurol. 2014 Aug;76(2):310-5. doi: 10.1002/ana.24215. Epub 2014 Jul 21.
• [13] Identifying and targeting determinants of melanoma cellular invasion.Oncotarget. 2016 Jul 5;7(27):41186-41202. doi: 10.18632/oncotarget.9227.
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• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] 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.
• [26] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [27] 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.
• [28] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [29] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] 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.
• [32] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [35] 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.
• [36] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [37] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.