Details of Drug Off-Target (DOT)

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

• DOT Name: TP53-regulated inhibitor of apoptosis 1 (TRIAP1)
• Synonyms: Protein 15E1.1; WF-1; p53-inducible cell-survival factor; p53CSV
• Gene Name: TRIAP1
• Related Disease:
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Osteosarcoma
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Diabetic kidney disease
  Epithelial ovarian cancer
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Prostate carcinoma
  Nasopharyngeal carcinoma
• UniProt ID: TRIA1_HUMAN
• PDB ID: 4XZS; 4XZV; 6I3V; 6I3Y; 6I4Y; 8AG0
• Pfam ID: PF05254
• Sequence:
  MNSVGEACTDMKREYDQCFNRWFAEKFLKGDSSGDPCTDLFKRYQQCVQKAIKEKEIPIE
  GLEFMGHGKEKPENSS
• Function: Involved in the modulation of the mitochondrial apoptotic pathway by ensuring the accumulation of cardiolipin (CL) in mitochondrial membranes. In vitro, the TRIAP1:PRELID1 complex mediates the transfer of phosphatidic acid (PA) between liposomes and probably functions as a PA transporter across the mitochondrion intermembrane space to provide PA for CL synthesis in the inner membrane. Likewise, the TRIAP1:PRELID3A complex mediates the transfer of phosphatidic acid (PA) between liposomes (in vitro) and probably functions as a PA transporter across the mitochondrion intermembrane space (in vivo). Mediates cell survival by inhibiting activation of caspase-9 which prevents induction of apoptosis.
• Reactome Pathway: TP53 Regulates Transcription of Genes Involved in Cytochrome C Release (R-HSA-6803204)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Definitive	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[3]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	TP53-regulated inhibitor of apoptosis 1 (TRIAP1) affects the response to substance of Josamycin.	[30]

23 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 TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[20]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[21]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[22]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[23]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[23]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[23]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[24]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[22]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[23]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[28]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of TP53-regulated inhibitor of apoptosis 1 (TRIAP1).	[17]

References

• [1] miR-1301/TRIAP1 Axis Participates in Epirubicin-Mediated Anti-Proliferation and Pro-Apoptosis in Osteosarcoma.Yonsei Med J. 2019 Sep;60(9):832-841. doi: 10.3349/ymj.2019.60.9.832.
• [2] Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance.Oncol Rep. 2015 Jul;34(1):415-22. doi: 10.3892/or.2015.3988. Epub 2015 May 19.
• [3] miRNA-125a-5p inhibits hepatocellular carcinoma cell proliferation and induces apoptosis by targeting TP53 regulated inhibitor of apoptosis 1 and Bcl-2-like-2 protein.Exp Ther Med. 2019 Aug;18(2):1196-1202. doi: 10.3892/etm.2019.7674. Epub 2019 Jun 14.
• [4] High TRIAP1 expression in penile carcinoma is associated with high risk of recurrence and poor survival.Ann Transl Med. 2019 Jul;7(14):330. doi: 10.21037/atm.2019.06.47.
• [5] MicroRNA-15a-5p down-regulation inhibits cervical cancer by targeting TP53INP1 in vitro.Eur Rev Med Pharmacol Sci. 2019 Oct;23(19):8219-8229. doi: 10.26355/eurrev_201910_19129.
• [6] MicroRNA-770-5p is involved in the development of diabetic nephropathy through regulating podocyte apoptosis by targeting TP53 regulated inhibitor of apoptosis 1.Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1248-1256. doi: 10.26355/eurrev_201902_17018.
• [7] MicroRNA-18a inhibits ovarian cancer growth via directly targeting TRIAP1 and IPMK.Oncol Lett. 2017 Jun;13(6):4039-4046. doi: 10.3892/ol.2017.5961. Epub 2017 Mar 31.
• [8] An integrated bioinformatical analysis of miR-19a target genes in multiple myeloma.Exp Ther Med. 2017 Nov;14(5):4711-4720. doi: 10.3892/etm.2017.5173. Epub 2017 Sep 21.
• [9] Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1.J Clin Med. 2019 Mar 12;8(3):348. doi: 10.3390/jcm8030348.
• [10] Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma.PLoS Genet. 2016 Jul 18;12(7):e1006183. doi: 10.1371/journal.pgen.1006183. eCollection 2016 Jul.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] 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.
• [19] 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.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Apoptosis, cell cycle progression and gene expression in TP53-depleted HCT116 colon cancer cells in response to short-term 5-fluorouracil treatment. Int J Oncol. 2007 Dec;31(6):1491-500.
• [22] Differential expression of TP53 associated genes in Fanconi anemia cells after mitomycin C and hydroxyurea treatment. Mutat Res. 2008 Oct 30;656(1-2):1-7.
• [23] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [24] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [30] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.