Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0YAMC0)

• DOT Name: Neuropilin and tolloid-like protein 2 (NETO2)
• Synonyms: Brain-specific transmembrane protein containing 2 CUB and 1 LDL-receptor class A domains protein 2
• Gene Name: NETO2
• Related Disease:
  Advanced cancer
  Carcinoma
  Gastric cancer
  Neoplasm
  Pancreatic cancer
  Stomach cancer
  Nasopharyngeal carcinoma
• UniProt ID: NETO2_HUMAN
• Pfam ID: PF00431 ; PF00057
• Sequence:
  MALERLCSVLKVLLITVLVVEGIAVAQKTQDGQNIGIKHIPATQCGIWVRTSNGGHFASP
  NYPDSYPPNKECIYILEAAPRQRIELTFDEHYYIEPSFECRFDHLEVRDGPFGFSPLIDR
  YCGVKSPPLIRSTGRFMWIKFSSDEELEGLGFRAKYSFIPDPDFTYLGGILNPIPDCQFE
  LSGADGIVRSSQVEQEEKTKPGQAVDCIWTIKATPKAKIYLRFLDYQMEHSNECKRNFVA
  VYDGSSSIENLKAKFCSTVANDVMLKTGIGVIRMWADEGSRLSRFRMLFTSFVEPPCTSS
  TFFCHSNMCINNSLVCNGVQNCAYPWDENHCKEKKKAGVFEQITKTHGTIIGITSGIVLV
  LLIISILVQVKQPRKKVMACKTAFNKTGFQEVFDPPHYELFSLRDKEISADLADLSEELD
  NYQKMRRSSTASRCIHDHHCGSQASSVKQSRTNLSSMELPFRNDFAQPQPMKTFNSTFKK
  SSYTFKQGHECPEQALEDRVMEEIPCEIYVRGREDSAQASISIDF
• Function: Accessory subunit of neuronal kainate-sensitive glutamate receptors, GRIK2 and GRIK3. Increases kainate-receptor channel activity, slowing the decay kinetics of the receptors, without affecting their expression at the cell surface, and increasing the open probability of the receptor channels. Modulates the agonist sensitivity of kainate receptors. Slows the decay of kainate receptor-mediated excitatory postsynaptic currents (EPSCs), thus directly influencing synaptic transmission.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	moderate	Altered Expression	[2]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[2]
Neoplasm	DISZKGEW	moderate	Altered Expression	[2]
Pancreatic cancer	DISJC981	moderate	Biomarker	[3]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[2]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Neuropilin and tolloid-like protein 2 (NETO2) affects the response to substance of Fluorouracil.	[26]

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 Neuropilin and tolloid-like protein 2 (NETO2).	[5]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the acetylation of Neuropilin and tolloid-like protein 2 (NETO2).	[25]

20 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 Neuropilin and tolloid-like protein 2 (NETO2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[15]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[16]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[17]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Neuropilin and tolloid-like protein 2 (NETO2).	[24]

References

• [1] Upregulation of NETO2 gene in colorectal cancer.BMC Genet. 2017 Dec 28;18(Suppl 1):117. doi: 10.1186/s12863-017-0581-8.
• [2] NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-B/Snail axis and predicts outcome of the patients.Cell Death Dis. 2019 Feb 15;10(3):162. doi: 10.1038/s41419-019-1388-5.
• [3] NETO2 promotes pancreatic cancer cell proliferation, invasion and migration via activation of the STAT3 signaling pathway.Cancer Manag Res. 2019 Jun 6;11:5147-5156. doi: 10.2147/CMAR.S204260. eCollection 2019.
• [4] Reducing NETO2 expression prevents human nasopharyngeal carcinoma (NPC) progression by suppressing metastasis and inducingapoptosis.Biochem Biophys Res Commun. 2019 May 28;513(2):494-501. doi: 10.1016/j.bbrc.2019.03.061. Epub 2019 Apr 8.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [17] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [18] 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.
• [19] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.