Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT15YWU7)

• DOT Name: Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1)
• Synonyms: B7 homolog 6; B7-H6
• Gene Name: NCR3LG1
• Related Disease:
  Adult lymphoma
  Advanced cancer
  B-cell neoplasm
  Carcinoma
  Cytomegalovirus infection
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gastric neoplasm
  Gestational trophoblastic neoplasia
  Glioma
  Hepatocellular carcinoma
  Lymphoma
  Neoplasm
  Pediatric lymphoma
  Promyelocytic leukaemia
  Stomach cancer
  Triple negative breast cancer
  Melanoma
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Esophageal cancer
  Liver cancer
  Metastatic malignant neoplasm
  Squamous cell carcinoma
• UniProt ID: NR3L1_HUMAN
• PDB ID: 3PV6; 3PV7; 4ZSO; 6YJP
• Pfam ID: PF07654
• Sequence:
  MTWRAAASTCAALLILLWALTTEGDLKVEMMAGGTQITPLNDNVTIFCNIFYSQPLNITS
  MGITWFWKSLTFDKEVKVFEFFGDHQEAFRPGAIVSPWRLKSGDASLRLPGIQLEEAGEY
  RCEVVVTPLKAQGTVQLEVVASPASRLLLDQVGMKENEDKYMCESSGFYPEAINITWEKQ
  TQKFPHPIEISEDVITGPTIKNMDGTFNVTSCLKLNSSQEDPGTVYQCVVRHASLHTPLR
  SNFTLTAARHSLSETEKTDNFSIHWWPISFIGVGLVLLIVLIPWKKICNKSSSAYTPLKC
  ILKHWNSFDTQTLKKEHLIFFCTRAWPSYQLQDGEAWPPEGSVNINTIQQLDVFCRQEGK
  WSEVPYVQAFFALRDNPDLCQCCRIDPALLTVTSGKSIDDNSTKSEKQTPREHSDAVPDA
  PILPVSPIWEPPPATTSTTPVLSSQPPTLLLPLQ
• Function: Triggers NCR3-dependent natural killer cell activation.
• Tissue Specificity: Not detected in any normal tissue tested. Expressed at the surface of several tumor cell lines including T and B-lymphomas, myeloid leukemias, melanomas, carcinomas and large T SV40 antigen-transformed cells (at protein level).
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[4]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[9]
Lymphoma	DISN6V4S	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[1]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[12]
Melanoma	DIS1RRCY	moderate	Altered Expression	[13]
Breast cancer	DIS7DPX1	Limited	Biomarker	[14]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[14]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[15]
Esophageal cancer	DISGB2VN	Limited	Altered Expression	[15]
Liver cancer	DISDE4BI	Limited	Biomarker	[15]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[16]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[17]

15 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 Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[25]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[26]
Promethazine	DM6I5GR	Approved	Promethazine increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1).	[30]

References

• [1] The B7 Family Member B7-H6: a New Bane of Tumor.Pathol Oncol Res. 2018 Oct;24(4):717-721. doi: 10.1007/s12253-017-0357-5. Epub 2017 Oct 31.
• [2] B7H6 is a functional ligand for NKp30 in rat and cattle and determines NKp30 reactivity toward human cancer cell lines.Eur J Immunol. 2019 Jan;49(1):54-65. doi: 10.1002/eji.201847746. Epub 2018 Dec 13.
• [3] Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma.Int J Oncol. 2016 Apr;48(4):1561-70. doi: 10.3892/ijo.2016.3393. Epub 2016 Feb 17.
• [4] B7-H6 protein expression has no prognostic significance in human gastric carcinoma.Pathol Oncol Res. 2014 Jan;20(1):203-7. doi: 10.1007/s12253-013-9686-1. Epub 2013 Nov 16.
• [5] Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20.Sci Rep. 2017 Aug 17;7(1):8661. doi: 10.1038/s41598-017-08866-2.
• [6] The prognostic value of B7-H6 in esophageal squamous cell carcinoma.Sci Rep. 2019 Dec 2;9(1):18122. doi: 10.1038/s41598-019-54731-9.
• [7] PD-L1, B7-H3 and VISTA are highly expressed in gestational trophoblastic neoplasia.Histopathology. 2019 Sep;75(3):421-430. doi: 10.1111/his.13882. Epub 2019 Jul 12.
• [8] B7-H6 expression is induced by lipopolysaccharide and facilitates cancer invasion and metastasis in human gliomas.Int Immunopharmacol. 2018 Jun;59:318-327. doi: 10.1016/j.intimp.2018.03.020. Epub 2018 Apr 18.
• [9] Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma.Hepatology. 2019 Mar;69(3):1165-1179. doi: 10.1002/hep.30235. Epub 2019 Feb 14.
• [10] The integrated stress response promotes B7H6 expression.J Mol Med (Berl). 2020 Jan;98(1):135-148. doi: 10.1007/s00109-019-01859-w. Epub 2019 Dec 14.
• [11] Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.Nat Commun. 2017 Sep 19;8(1):593. doi: 10.1038/s41467-017-00678-2.
• [12] Knockdown of B7H6 inhibits tumor progression in triple-negative breast cancer.Oncol Lett. 2018 Jul;16(1):91-96. doi: 10.3892/ol.2018.8689. Epub 2018 May 10.
• [13] Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30.Cancer Res. 2014 Jul 1;74(13):3429-40. doi: 10.1158/0008-5472.CAN-13-3017. Epub 2014 Apr 29.
• [14] Long non-coding RNA LINC00673 promotes breast cancer proliferation and metastasis through regulating B7-H6 and epithelial-mesenchymal transition.Am J Cancer Res. 2018 Jul 1;8(7):1273-1287. eCollection 2018.
• [15] Comprehensive molecular profiling of the B7 family in gastrointestinal cancer.Cell Prolif. 2018 Oct;51(5):e12468. doi: 10.1111/cpr.12468. Epub 2018 Jul 12.
• [16] B7-H6 expression in human hepatocellular carcinoma and its clinical significance [corrected].Cancer Cell Int. 2018 Sep 4;18:126. doi: 10.1186/s12935-018-0627-7. eCollection 2018.
• [17] The prognostic value of B7-H6 protein expression in human oral squamous cell carcinoma.J Oral Pathol Med. 2017 Oct;46(9):766-772. doi: 10.1111/jop.12586. Epub 2017 Jul 28.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] 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.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [22] 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.
• [23] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [24] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] Enhanced activation of human NK cells by drug-exposed hepatocytes. Arch Toxicol. 2020 Feb;94(2):439-448. doi: 10.1007/s00204-020-02668-8. Epub 2020 Feb 14.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [29] 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.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [31] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [32] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.