Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIPA4ZR)

• DOT Name: Thyroid receptor-interacting protein 6 (TRIP6)
• Synonyms: TR-interacting protein 6; TRIP-6; Opa-interacting protein 1; OIP-1; Zyxin-related protein 1; ZRP-1
• Gene Name: TRIP6
• Related Disease:
  Glioblastoma multiforme
  Neoplasm
  Adult glioblastoma
  Advanced cancer
  Bone Paget disease
  Colonic neoplasm
  Colorectal carcinoma
  Ewing sarcoma
  Paget's disease
  Hepatocellular carcinoma
  Malignant tumor of nasopharynx
  Nasopharyngeal carcinoma
  Neural tube defect
  Epithelioid mesothelioma
  Mesothelioma
• UniProt ID: TRIP6_HUMAN
• PDB ID: 1X61; 2DLO
• Pfam ID: PF00412
• Sequence:
  MSGPTWLPPKQPEPARAPQGRAIPRGTPGPPPAHGAALQPHPRVNFCPLPSEQCYQAPGG
  PEDRGPAWVGSHGVLQHTQGLPADRGGLRPGSLDAEIDLLSSTLAELNGGRGHASRRPDR
  QAYEPPPPPAYRTGSLKPNPASPLPASPYGGPTPASYTTASTPAGPAFPVQVKVAQPVRG
  CGPPRRGASQASGPLPGPHFPLPGRGEVWGPGYRSQREPGPGAKEEAAGVSGPAGRGRGG
  EHGPQVPLSQPPEDELDRLTKKLVHDMNHPPSGEYFGQCGGCGEDVVGDGAGVVALDRVF
  HVGCFVCSTCRAQLRGQHFYAVERRAYCEGCYVATLEKCATCSQPILDRILRAMGKAYHP
  GCFTCVVCHRGLDGIPFTVDATSQIHCIEDFHRKFAPRCSVCGGAIMPEPGQEETVRIVA
  LDRSFHIGCYKCEECGLLLSSEGECQGCYPLDGHILCKACSAWRIQELSATVTTDC
• Function: Relays signals from the cell surface to the nucleus to weaken adherens junction and promote actin cytoskeleton reorganization and cell invasiveness. Involved in lysophosphatidic acid-induced cell adhesion and migration. Acts as a transcriptional coactivator for NF-kappa-B and JUN, and mediates the transrepression of these transcription factors induced by glucocorticoid receptor.
• Tissue Specificity: Abundantly expressed in kidney, liver and lung. Lower levels in heart, placenta and pancreas. Expressed in colonic epithelial cells. Up-regulated in colonic tumors.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone Paget disease	DISIPS4V	Strong	Biomarker	[4]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[7]
Paget's disease	DISO3MC0	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[8]
Malignant tumor of nasopharynx	DISTGIGF	moderate	Biomarker	[9]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[9]
Neural tube defect	DIS5J95E	Disputed	Biomarker	[10]
Epithelioid mesothelioma	DIS17SNY	Limited	Altered Expression	[11]
Mesothelioma	DISKWK9M	Limited	Biomarker	[11]

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 Thyroid receptor-interacting protein 6 (TRIP6).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Thyroid receptor-interacting protein 6 (TRIP6).	[20]

12 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 Thyroid receptor-interacting protein 6 (TRIP6).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[16]
Selenium	DM25CGV	Approved	Selenium increases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[17]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[18]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Thyroid receptor-interacting protein 6 (TRIP6).	[24]

References

• [1] TRIP6 regulates p27 KIP1 to promote tumorigenesis.Mol Cell Biol. 2013 Apr;33(7):1394-409. doi: 10.1128/MCB.01149-12. Epub 2013 Jan 22.
• [2] TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/-Catenin Signaling.Cancer Res. 2019 Jul 1;79(13):3332-3346. doi: 10.1158/0008-5472.CAN-18-2986. Epub 2019 Apr 24.
• [3] Defining the role of TRIP6 in cell physiology and cancer.Biol Cell. 2011 Dec 1;103(12):573-91. doi: 10.1042/BC20110077.
• [4] Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity.J Cell Biochem. 2008 Jul 1;104(4):1500-8. doi: 10.1002/jcb.21723.
• [5] TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness.FASEB J. 2009 Mar;23(3):916-28. doi: 10.1096/fj.08-106344. Epub 2008 Nov 18.
• [6] TRIP6, as a target of miR-7, regulates the proliferation and metastasis of colorectal cancer cells.Biochem Biophys Res Commun. 2019 Jun 18;514(1):231-238. doi: 10.1016/j.bbrc.2019.04.092. Epub 2019 Apr 24.
• [7] The Zyxin-related protein thyroid receptor interacting protein 6 (TRIP6) is overexpressed in Ewing's sarcoma and promotes migration, invasion and cell growth.Biol Cell. 2013 Nov;105(11):535-47. doi: 10.1111/boc.201300041. Epub 2013 Sep 18.
• [8] TRIP6 promotes cell proliferation in hepatocellular carcinoma via suppression of FOXO3a.Biochem Biophys Res Commun. 2017 Dec 16;494(3-4):594-601. doi: 10.1016/j.bbrc.2017.10.117. Epub 2017 Oct 28.
• [9] Characterization of TRIP6-dependent nasopharyngeal cancer cell migration.Tumour Biol. 2013 Aug;34(4):2329-35. doi: 10.1007/s13277-013-0780-5. Epub 2013 Apr 11.
• [10] Valproic acid teratogenicity: a toxicogenomics approach.Environ Health Perspect. 2004 Aug;112(12):1225-35. doi: 10.1289/txg.7034.
• [11] Gene expression profile of aquaporin 1 and associated interactors in malignant pleural mesothelioma.Gene. 2013 Mar 15;517(1):99-105. doi: 10.1016/j.gene.2012.12.075. Epub 2013 Jan 9.
• [12] 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.
• [13] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [14] 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.
• [15] 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.
• [16] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [19] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [20] 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.
• [21] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [22] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.