Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF67VPH)

• DOT Name: Eukaryotic translation initiation factor 3 subunit B (EIF3B)
• Synonyms: eIF3b; Eukaryotic translation initiation factor 3 subunit 9; Prt1 homolog; hPrt1; eIF-3-eta; eIF3 p110; eIF3 p116
• Gene Name: EIF3B
• Related Disease:
  Gastric cancer
  Stomach cancer
  Advanced cancer
  Bladder cancer
  Carcinoma
  Chronic hepatitis B virus infection
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  HIV infectious disease
  Non-small-cell lung cancer
  Prostate carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adult glioblastoma
  Glioblastoma multiforme
  Neoplasm
  Prostate cancer
  Bone osteosarcoma
  Osteosarcoma
• UniProt ID: EIF3B_HUMAN
• PDB ID: 2KRB; 2NLW; 5K1H; 6YBT; 6ZMW; 6ZON; 6ZP4; 6ZVJ; 7A09; 7QP6; 7QP7
• Pfam ID: PF08662 ; PF00076
• Sequence:
  MQDAENVAVPEAAEERAEPGQQQPAAEPPPAEGLLRPAGPGAPEAAGTEASSEEVGIAEA
  GPESEVRTEPAAEAEAASGPSESPSPPAAEELPGSHAEPPVPAQGEAPGEQARDERSDSR
  AQAVSEDAGGNEGRAAEAEPRALENGDADEPSFSDPEDFVDDVSEEELLGDVLKDRPQEA
  DGIDSVIVVDNVPQVGPDRLEKLKNVIHKIFSKFGKITNDFYPEEDGKTKGYIFLEYASP
  AHAVDAVKNADGYKLDKQHTFRVNLFTDFDKYMTISDEWDIPEKQPFKDLGNLRYWLEEA
  ECRDQYSVIFESGDRTSIFWNDVKDPVSIEERARWTETYVRWSPKGTYLATFHQRGIALW
  GGEKFKQIQRFSHQGVQLIDFSPCERYLVTFSPLMDTQDDPQAIIIWDILTGHKKRGFHC
  ESSAHWPIFKWSHDGKFFARMTLDTLSIYETPSMGLLDKKSLKISGIKDFSWSPGGNIIA
  FWVPEDKDIPARVTLMQLPTRQEIRVRNLFNVVDCKLHWQKNGDYLCVKVDRTPKGTQGV
  VTNFEIFRMREKQVPVDVVEMKETIIAFAWEPNGSKFAVLHGEAPRISVSFYHVKNNGKI
  ELIKMFDKQQANTIFWSPQGQFVVLAGLRSMNGALAFVDTSDCTVMNIAEHYMASDVEWD
  PTGRYVVTSVSWWSHKVDNAYWLWTFQGRLLQKNNKDRFCQLLWRPRPPTLLSQEQIKQI
  KKDLKKYSKIFEQKDRLSQSKASKELVERRRTMMEDFRKYRKMAQELYMEQKNERLELRG
  GVDTDELDSNVDDWEEETIEFFVTEEIIPLGNQE
• Function: RNA-binding 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 ; (Microbial infection) In case of FCV infection, plays a role in the ribosomal termination-reinitiation event leading to the translation of VP2.
• 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

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Altered Expression	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[10]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[11]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Prostate cancer	DISF190Y	moderate	Altered Expression	[11]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[10]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[10]

23 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 B (EIF3B).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[20]
Selenium	DM25CGV	Approved	Selenium increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[21]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[22]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[19]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[23]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[30]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of Eukaryotic translation initiation factor 3 subunit B (EIF3B).	[25]

References

• [1] EIF3B is associated with poor outcomes in gastric cancer patients and promotes cancer progression via the PI3K/AKT/mTOR signaling pathway.Cancer Manag Res. 2019 Aug 21;11:7877-7891. doi: 10.2147/CMAR.S207834. eCollection 2019.
• [2] The Biological Roles of Translation Initiation Factor 3b.Int J Biol Sci. 2018 Sep 7;14(12):1630-1635. doi: 10.7150/ijbs.26932. eCollection 2018.
• [3] Translation initiation factor eIF3b expression in human cancer and its role in tumor growth and lung colonization.Clin Cancer Res. 2013 Jun 1;19(11):2850-60. doi: 10.1158/1078-0432.CCR-12-3084. Epub 2013 Apr 10.
• [4] EIF3B correlates with advanced disease stages and poor prognosis, and it promotes proliferation and inhibits apoptosis in non-small cell lung cancer.Cancer Biomark. 2018;23(2):291-300. doi: 10.3233/CBM-181628.
• [5] New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors.Eur J Cancer. 2017 Sep;83:56-70. doi: 10.1016/j.ejca.2017.06.003. Epub 2017 Jul 14.
• [6] Eukaryotic Translation Initiation Factor 3b is both a Promising Prognostic Biomarker and a Potential Therapeutic Target for Patients with Clear Cell Renal Cell Carcinoma.J Cancer. 2017 Sep 2;8(15):3049-3061. doi: 10.7150/jca.19594. eCollection 2017.
• [7] RNA interference-mediated silencing of eukaryotic translation initiation factor 3, subunit B (EIF3B) gene expression inhibits proliferation of colon cancer cells.World J Surg Oncol. 2012 Jun 26;10:119. doi: 10.1186/1477-7819-10-119.
• [8] TEX9 and eIF3b functionally synergize to promote the progression of esophageal squamous cell carcinoma.BMC Cancer. 2019 Sep 3;19(1):875. doi: 10.1186/s12885-019-6071-9.
• [9] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [10] Silencing of translation initiation factor eIF3b promotes apoptosis in osteosarcoma cells.Bone Joint Res. 2017 Mar;6(3):186-193. doi: 10.1302/2046-3758.63.BJR-2016-0151.R2.
• [11] Inhibition of eukaryotic initiation factor 3B suppresses proliferation and promotes apoptosis of chronic myeloid leukemia cells.Adv Clin Exp Med. 2019 Dec;28(12):1639-1645. doi: 10.17219/acem/110323.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Comparison of the gene expression profiles of monocytic versus granulocytic lineages of HL-60 leukemia cell differentiation by DNA microarray analysis. Life Sci. 2003 Aug 15;73(13):1705-19. doi: 10.1016/s0024-3205(03)00515-0.
• [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] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis. Int J Cancer. 2004 Mar 20;109(2):220-9. doi: 10.1002/ijc.11692.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [20] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [24] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [25] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [26] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [27] 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.
• [28] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [29] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.