Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTVT4MB)

• DOT Name: Tumor necrosis factor receptor superfamily member 19 (TNFRSF19)
• Synonyms: TRADE; Toxicity and JNK inducer
• Gene Name: TNFRSF19
• Related Disease:
  Gastric cancer
  Multiple sclerosis
  Stomach cancer
  Colorectal carcinoma
  Colorectal neoplasm
  Glioma
  Intestinal neoplasm
  Lung cancer
  Lung carcinoma
  Melanoma
  Nasopharyngeal carcinoma
  Neoplasm
  Vascular dementia
  Advanced cancer
  Adult glioblastoma
  Glioblastoma multiforme
  Nervous system inflammation
• UniProt ID: TNR19_HUMAN
• Sequence:
  MALKVLLEQEKTFFTLLVLLGYLSCKVTCESGDCRQQEFRDRSGNCVPCNQCGPGMELSK
  ECGFGYGEDAQCVTCRLHRFKEDWGFQKCKPCLDCAVVNRFQKANCSATSDAICGDCLPG
  FYRKTKLVGFQDMECVPCGDPPPPYEPHCASKVNLVKIASTASSPRDTALAAVICSALAT
  VLLALLILCVIYCKRQFMEKKPSWSLRSQDIQYNGSELSCFDRPQLHEYAHRACCQCRRD
  SVQTCGPVRLLPSMCCEEACSPNPATLGCGVHSAASLQARNAGPAGEMVPTFFGSLTQSI
  CGEFSDAWPLMQNPMGGDNISFCDSYPELTGEDIHSLNPELESSTSLDSNSSQDLVGGAV
  PVQSHSENFTAATDLSRYNNTLVESASTQDALTMRSQLDQESGAVIHPATQTSLQVRQRL
  GSL
• Function: Can mediate activation of JNK and NF-kappa-B. May promote caspase-independent cell death.
• Tissue Specificity: Highly expressed in prostate. Detected at lower levels in thymus, spleen, testis, uterus, small intestine, colon and peripheral blood leukocytes.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Definitive	Altered Expression	[2]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Intestinal neoplasm	DISK0GUH	Strong	Altered Expression	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Melanoma	DIS1RRCY	Strong	Biomarker	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Vascular dementia	DISVO82H	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[11]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[12]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) affects the response to substance of Temozolomide.	[39]
DTI-015	DMXZRW0	Approved	Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) affects the response to substance of DTI-015.	[39]

30 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 Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[21]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[22]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[24]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[25]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[26]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[24]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[27]
Docetaxel	DMDI269	Approved	Docetaxel decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[28]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[29]
Pracinostat	DMTD7AB	Phase 3	Pracinostat increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[32]
Scriptaid	DM9JZ21	Preclinical	Scriptaid increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[34]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[35]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[36]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal decreases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[37]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid increases the expression of Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[38]

1 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 Tumor necrosis factor receptor superfamily member 19 (TNFRSF19).	[30]

References

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• [2] TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions.Neuropathol Appl Neurobiol. 2007 Feb;33(1):99-107. doi: 10.1111/j.1365-2990.2006.00787.x.
• [3] TROY is a promising prognostic biomarker in patients with colorectal cancer.Oncol Lett. 2018 Apr;15(4):5989-5994. doi: 10.3892/ol.2018.8079. Epub 2018 Feb 16.
• [4] -catenin regulates NF-B activity via TNFRSF19 in colorectal cancer cells.Int J Cancer. 2014 Oct 15;135(8):1800-11. doi: 10.1002/ijc.28839. Epub 2014 Apr 1.
• [5] TROY interacts with RKIP to promote glioma development.Oncogene. 2019 Feb;38(9):1544-1559. doi: 10.1038/s41388-018-0503-x. Epub 2018 Oct 18.
• [6] Troy, a tumor necrosis factor receptor family member, interacts with lgr5 to inhibit wnt signaling in intestinal stem cells.Gastroenterology. 2013 Feb;144(2):381-391. doi: 10.1053/j.gastro.2012.10.048. Epub 2012 Nov 7.
• [7] The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression.Genome Biol. 2019 May 24;20(1):103. doi: 10.1186/s13059-019-1696-1.
• [8] Tumor necrosis factor receptor superfamily member TROY is a novel melanoma biomarker and potential therapeutic target.Int J Cancer. 2007 Mar 15;120(6):1304-10. doi: 10.1002/ijc.22367.
• [9] TNFRSF19 Inhibits TGF Signaling through Interaction with TGF Receptor Type I to Promote Tumorigenesis.Cancer Res. 2018 Jul 1;78(13):3469-3483. doi: 10.1158/0008-5472.CAN-17-3205. Epub 2018 May 7.
• [10] A strong synergistic epistasis between FAM134B and TNFRSF19 on the susceptibility to vascular dementia.Psychiatr Genet. 2011 Feb;21(1):37-41. doi: 10.1097/YPG.0b013e3283413496.
• [11] A Novel Signaling Complex between TROY and EGFR Mediates Glioblastoma Cell Invasion.Mol Cancer Res. 2018 Feb;16(2):322-332. doi: 10.1158/1541-7786.MCR-17-0454. Epub 2017 Nov 8.
• [12] p75NTR and TROY: Uncharted Roles of Nogo Receptor Complex in Experimental Autoimmune Encephalomyelitis.Mol Neurobiol. 2018 Aug;55(8):6329-6336. doi: 10.1007/s12035-017-0841-7. Epub 2018 Jan 2.
• [13] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [14] 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.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [19] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [20] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [21] 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.
• [22] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [23] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [24] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [25] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [26] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [27] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [30] 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.
• [31] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [32] 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.
• [33] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [34] 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.
• [35] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [36] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [37] Prolyl endopeptidase is involved in cellular signalling in human neuroblastoma SH-SY5Y cells. Neurosignals. 2011;19(2):97-109. doi: 10.1159/000326342. Epub 2011 Apr 10.
• [38] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.
• [39] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.