Details of Drug Off-Target (DOT)

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

• DOT Name: Eukaryotic translation initiation factor 6 (EIF6)
• Synonyms: eIF-6; B(2)GCN homolog; B4 integrin interactor; CAB; p27(BBP)
• Gene Name: EIF6
• Related Disease:
  Metabolic disorder
  Ovarian cancer
  Ovarian neoplasm
  Adenocarcinoma
  Adenoma
  Adult lymphoma
  Advanced cancer
  Biliary tract cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chronic hepatitis B virus infection
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Gallbladder cancer
  Gallbladder carcinoma
  Head and neck carcinoma
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  leukaemia
  Leukemia
  Leukopenia
  Lung cancer
  Lung carcinoma
  Lymphoma
  Malignant pleural mesothelioma
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Pediatric lymphoma
  Pulmonary fibrosis
  Rectal carcinoma
  Skin cancer
  Sleep disorder
  Squamous cell carcinoma
  Thrombocytopenia
  Carcinoma
  Gastric cancer
  Stomach cancer
  Neuroblastoma
  Metastatic malignant neoplasm
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Shwachman-Diamond syndrome
• UniProt ID: IF6_HUMAN
• PDB ID: 6LQM ; 6LSR ; 6LSS ; 6LU8 ; 7OW7 ; 8A3D ; 8FKP ; 8FKQ ; 8FKR ; 8FKS ; 8FKT ; 8FKU ; 8FKV ; 8FKW ; 8FKX ; 8FKY ; 8FKZ ; 8FL0 ; 8FL2 ; 8FL3 ; 8FL4 ; 8FL6 ; 8FL7 ; 8FL9 ; 8FLA ; 8FLB ; 8FLC ; 8FLD ; 8FLE ; 8FLF ; 8IDT ; 8IDY ; 8IE3 ; 8INE ; 8INF ; 8INK ; 8IPD ; 8IPX ; 8IPY ; 8IR1 ; 8IR3
• Pfam ID: PF01912
• Sequence:
  MAVRASFENNCEIGCFAKLTNTYCLVAIGGSENFYSVFEGELSDTIPVVHASIAGCRIIG
  RMCVGNRHGLLVPNNTTDQELQHIRNSLPDTVQIRRVEERLSALGNVTTCNDYVALVHPD
  LDRETEEILADVLKVEVFRQTVADQVLVGSYCVFSNQGGLVHPKTSIEDQDELSSLLQVP
  LVAGTVNRGSEVIAAGMVVNDWCAFCGLDTTSTELSVVESVFKLNEAQPSTIATSMRDSL
  IDSLT
• Function: Binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit to form the 80S initiation complex in the cytoplasm. Behaves as a stimulatory translation initiation factor downstream insulin/growth factors. Is also involved in ribosome biogenesis. Associates with pre-60S subunits in the nucleus and is involved in its nuclear export. Cytoplasmic release of TIF6 from 60S subunits and nuclear relocalization is promoted by a RACK1 (RACK1)-dependent protein kinase C activity. In tissues responsive to insulin, controls fatty acid synthesis and glycolysis by exerting translational control of adipogenic transcription factors such as CEBPB, CEBPD and ATF4 that have G/C rich or uORF in their 5'UTR. Required for ROS-dependent megakaryocyte maturation and platelets formation, controls the expression of mitochondrial respiratory chain genes involved in reactive oxygen species (ROS) synthesis. Involved in miRNA-mediated gene silencing by the RNA-induced silencing complex (RISC). Required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC. Modulates cell cycle progression and global translation of pre-B cells, its activation seems to be rate-limiting in tumorigenesis and tumor growth.
• Tissue Specificity: Expressed at very high levels in colon carcinoma with lower levels in normal colon and ileum and lowest levels in kidney and muscle (at protein level).
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[1]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Biliary tract cancer	DISBNYQL	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[8]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[11]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Gallbladder cancer	DISXJUAF	Strong	Biomarker	[7]
Gallbladder carcinoma	DISD6ACL	Strong	Biomarker	[7]
Head and neck carcinoma	DISOU1DS	Strong	Altered Expression	[12]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[9]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[9]
HIV infectious disease	DISO97HC	Strong	Biomarker	[13]
leukaemia	DISS7D1V	Strong	Genetic Variation	[14]
Leukemia	DISNAKFL	Strong	Genetic Variation	[14]
Leukopenia	DISJMBMM	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Lymphoma	DISN6V4S	Strong	Biomarker	[5]
Malignant pleural mesothelioma	DIST2R60	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Altered Expression	[17]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[5]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[18]
Rectal carcinoma	DIS8FRR7	Strong	Biomarker	[19]
Skin cancer	DISTM18U	Strong	Biomarker	[20]
Sleep disorder	DIS3JP1U	Strong	Biomarker	[21]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[3]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[15]
Carcinoma	DISH9F1N	moderate	Altered Expression	[22]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[23]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[23]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[24]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[25]
Pancreatic cancer	DISJC981	Limited	Biomarker	[25]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[25]
Shwachman-Diamond syndrome	DISW57NW	Limited	Autosomal dominant	[26]

4 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 Eukaryotic translation initiation factor 6 (EIF6).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Eukaryotic translation initiation factor 6 (EIF6).	[33]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eukaryotic translation initiation factor 6 (EIF6).	[34]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Eukaryotic translation initiation factor 6 (EIF6).	[35]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[28]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[29]
Selenium	DM25CGV	Approved	Selenium increases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[30]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[31]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[32]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[31]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[36]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[37]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Eukaryotic translation initiation factor 6 (EIF6).	[38]

References

• [1] Translational control by mTOR-independent routes: how eIF6 organizes metabolism.Biochem Soc Trans. 2016 Dec 15;44(6):1667-1673. doi: 10.1042/BST20160179.
• [2] eIF3a improve cisplatin sensitivity in ovarian cancer by regulating XPC and p27Kip1 translation.Oncotarget. 2015 Sep 22;6(28):25441-51. doi: 10.18632/oncotarget.4555.
• [3] Influence of eukaryotic translation initiation factor 6 on non-small cell lung cancer development and progression.Eur J Cancer. 2018 Sep;101:165-180. doi: 10.1016/j.ejca.2018.07.001. Epub 2018 Aug 1.
• [4] Expression of a highly conserved protein, p27BBP, during the progression of human colorectal cancer.Cancer Res. 2000 Feb 1;60(3):510-6.
• [5] Expression and activity of eIF6 trigger malignant pleural mesothelioma growth in vivo.Oncotarget. 2015 Nov 10;6(35):37471-85. doi: 10.18632/oncotarget.5462.
• [6] Increased HE4 mRNA Expression Correlates with High Level Of eIF3a mRNA And Better Survival in Women with Epithelial Ovarian Cancer.J Cancer. 2018 Feb 28;9(6):1088-1095. doi: 10.7150/jca.23639. eCollection 2018.
• [7] Eukaryotic translation initiation factor 6 overexpression plays a major role in the translational control of gallbladder cancer.J Cancer Res Clin Oncol. 2019 Nov;145(11):2699-2711. doi: 10.1007/s00432-019-03030-x. Epub 2019 Oct 4.
• [8] An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer.Nat Genet. 2014 Oct;46(10):1051-9. doi: 10.1038/ng.3073. Epub 2014 Aug 24.
• [9] 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.
• [10] eIF6 Promotes Colorectal Cancer Proliferation and Invasion by Regulating AKT-Related Signaling Pathways.J Biomed Nanotechnol. 2019 Jul 1;15(7):1556-1567. doi: 10.1166/jbn.2019.2792.
• [11] The Prognostic Significance of Eukaryotic Translation Initiation Factors (eIFs) in Endometrial Cancer.Int J Mol Sci. 2019 Dec 6;20(24):6169. doi: 10.3390/ijms20246169.
• [12] The role of eukaryotic translation initiation factor 6 in tumors.Oncol Lett. 2017 Jul;14(1):3-9. doi: 10.3892/ol.2017.6161. Epub 2017 May 12.
• [13] 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.
• [14] Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.Genes Dev. 2011 May 1;25(9):917-29. doi: 10.1101/gad.623011.
• [15] Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.Br J Haematol. 2019 Mar;184(6):974-981. doi: 10.1111/bjh.15729. Epub 2018 Dec 26.
• [16] HE4 and eIF3a Expression Correlates with Surgical Outcome and Overall Survival in Ovarian Cancer Patients with Secondary Cytoreduction.J Cancer. 2018 Jun 14;9(14):2472-2479. doi: 10.7150/jca.25184. eCollection 2018.
• [17] High levels of eukaryotic Initiation Factor 6 (eIF6) are required for immune system homeostasis and for steering the glycolytic flux of TCR-stimulated CD4(+) T cells in both mice and humans.Dev Comp Immunol. 2017 Dec;77:69-76. doi: 10.1016/j.dci.2017.07.022. Epub 2017 Jul 22.
• [18] Inhibitory effect of l-mimosine on bleomycin-induced pulmonary fibrosis in rats: Role of eIF3a and p27.Int Immunopharmacol. 2015 Jul;27(1):53-64. doi: 10.1016/j.intimp.2015.04.048. Epub 2015 May 5.
• [19] Separation of low and high grade colon and rectum carcinoma by eukaryotic translation initiation factors 1, 5 and 6.Oncotarget. 2017 Sep 5;8(60):101224-101243. doi: 10.18632/oncotarget.20642. eCollection 2017 Nov 24.
• [20] Design, Synthesis, and Biological Evaluation of Polyaminocarboxylate Ligand-Based Theranostic Conjugates for Antibody-Targeted Cancer Therapy and Near-Infrared Optical Imaging.ChemMedChem. 2018 Dec 20;13(24):2606-2617. doi: 10.1002/cmdc.201800598. Epub 2018 Nov 26.
• [21] Factors Associated with Potassium-Competitive Acid Blocker Non-Response in Patients with Proton Pump Inhibitor-Refractory Gastroesophageal Reflux Disease.Digestion. 2017;95(4):281-287. doi: 10.1159/000475658. Epub 2017 May 13.
• [22] Overexpression of p27BBP in head and neck carcinomas and their lymph node metastases.Head Neck. 2004 May;26(5):408-17. doi: 10.1002/hed.10401.
• [23] Impact of a Eukaryotic Translation Initiation Factor 3a Polymorphism on Susceptibility to Gastric Cancer.Med Princ Pract. 2016;25(5):461-5. doi: 10.1159/000447741. Epub 2016 Jun 22.
• [24] Polypyrrole-coated cellulose nanofibers: influence of orientation, coverage and electrical stimulation on SH-SY5Y behavior.J Mater Chem B. 2019 Nov 14;7(42):6500-6507. doi: 10.1039/c9tb01300h. Epub 2019 Oct 2.
• [25] Eukaryotic Translation Initiation Factor 3a (eIF3a) Promotes Cell Proliferation and Motility in Pancreatic Cancer.J Korean Med Sci. 2016 Oct;31(10):1586-94. doi: 10.3346/jkms.2016.31.10.1586.
• [26] Heterozygous missense variant in EIF6 gene: A novel form of Shwachman-Diamond syndrome?. Am J Med Genet A. 2020 Sep;182(9):2010-2020. doi: 10.1002/ajmg.a.61758. Epub 2020 Jul 13.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [32] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [33] 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.
• [34] 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.
• [35] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [36] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [38] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.