Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE07WND)

• DOT Name: Eukaryotic translation initiation factor 3 subunit I (EIF3I)
• Synonyms: eIF3i; Eukaryotic translation initiation factor 3 subunit 2; TGF-beta receptor-interacting protein 1; TRIP-1; eIF-3-beta; eIF3 p36
• Gene Name: EIF3I
• Related Disease:
  Adult hepatocellular carcinoma
  Advanced cancer
  Carcinoma
  Colon cancer
  Colonic neoplasm
  Glioma
  Hepatocellular carcinoma
  Liver cancer
  Metastatic malignant neoplasm
  Neoplasm
  Neuroblastoma
  Melanoma
• UniProt ID: EIF3I_HUMAN
• PDB ID: 6YBT; 6ZMW; 6ZON; 6ZP4; 6ZVJ; 7A09
• Pfam ID: PF12894 ; PF00400
• Sequence:
  MKPILLQGHERSITQIKYNREGDLLFTVAKDPIVNVWYSVNGERLGTYMGHTGAVWCVDA
  DWDTKHVLTGSADNSCRLWDCETGKQLALLKTNSAVRTCGFDFGGNIIMFSTDKQMGYQC
  FVSFFDLRDPSQIDNNEPYMKIPCNDSKITSAVWGPLGECIIAGHESGELNQYSAKSGEV
  LVNVKEHSRQINDIQLSRDMTMFVTASKDNTAKLFDSTTLEHQKTFRTERPVNSAALSPN
  YDHVVLGGGQEAMDVTTTSTRIGKFEARFFHLAFEEEFGRVKGHFGPINSVAFHPDGKSY
  SSGGEDGYVRIHYFDPQYFEFEFEA
• Function: Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression.
• Reactome Pathway:
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult hepatocellular carcinoma	DIS6ZPAI	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Liver cancer	DISDE4BI	Strong	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[7]
Melanoma	DIS1RRCY	Limited	Biomarker	[2]

14 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 Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[14]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[15]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[21]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[22]

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 Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eukaryotic translation initiation factor 3 subunit I (EIF3I).	[17]

References

• [1] The translation initiation factor eIF3i up-regulates vascular endothelial growth factor A, accelerates cell proliferation, and promotes angiogenesis in embryonic development and tumorigenesis.J Biol Chem. 2014 Oct 10;289(41):28310-23. doi: 10.1074/jbc.M114.571356. Epub 2014 Aug 21.
• [2] Cancer Targeted Gene Therapy for Inhibition of Melanoma Lung Metastasis with eIF3i shRNA Loaded Liposomes.Mol Pharm. 2020 Jan 6;17(1):229-238. doi: 10.1021/acs.molpharmaceut.9b00943. Epub 2019 Dec 10.
• [3] Carcinoma-associated eIF3i overexpression facilitates mTOR-dependent growth transformation.Mol Carcinog. 2006 Dec;45(12):957-67. doi: 10.1002/mc.20269.
• [4] EIF3i promotes colon oncogenesis by regulating COX-2 protein synthesis and -catenin activation.Oncogene. 2014 Aug 7;33(32):4156-63. doi: 10.1038/onc.2013.397. Epub 2013 Sep 23.
• [5] Systematically profiling the expression of eIF3 subunits in glioma reveals the expression of eIF3i has prognostic value in IDH-mutant lower grade glioma.Cancer Cell Int. 2019 Jun 4;19:155. doi: 10.1186/s12935-019-0867-1. eCollection 2019.
• [6] Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma.Oncotarget. 2015 Feb 20;6(5):2903-16. doi: 10.18632/oncotarget.3093.
• [7] Expression of co-factors (SMRT and Trip-1) for retinoic acid receptors in human neuroectodermal cell lines.Biochem Biophys Res Commun. 1997 May 8;234(1):278-82. doi: 10.1006/bbrc.1997.6626.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [14] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [15] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [16] 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.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] 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.
• [19] Proteomic signatures in thapsigargin-treated hepatoma cells. Chem Res Toxicol. 2011 Aug 15;24(8):1215-22. doi: 10.1021/tx200109y. Epub 2011 Jul 1.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.