Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT08H03R)

DOT Name Eukaryotic initiation factor 4A-II (EIF4A2)
Synonyms eIF-4A-II; eIF4A-II; EC 3.6.4.13; ATP-dependent RNA helicase eIF4A-2
Gene Name EIF4A2
Related Disease
Meningioma ( )
T-cell acute lymphoblastic leukaemia ( )
Triple negative breast cancer ( )
Adult lymphoma ( )
Advanced cancer ( )
Alzheimer disease ( )
B-cell lymphoma ( )
B-cell neoplasm ( )
Breast carcinoma ( )
Chikungunya virus infection ( )
Colonic neoplasm ( )
Colorectal carcinoma ( )
Colorectal neoplasm ( )
Cytomegalovirus infection ( )
Esophageal adenocarcinoma ( )
Familial multiple trichoepithelioma ( )
Herpes simplex infection ( )
Immunodeficiency ( )
Leukemia ( )
Lung cancer ( )
Lung carcinoma ( )
Lymphoma ( )
Lymphoma, non-Hodgkin, familial ( )
Malignant glioma ( )
Malignant peripheral nerve sheath tumor ( )
Matthew-Wood syndrome ( )
Medulloblastoma ( )
Mesothelioma ( )
Metastatic malignant neoplasm ( )
Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures ( )
Non-hodgkin lymphoma ( )
Pancreatic cancer ( )
Pediatric lymphoma ( )
Schizophrenia ( )
Carcinoma ( )
Influenza ( )
Pancreatic ductal carcinoma ( )
Patent ductus arteriosus ( )
Breast cancer ( )
Melanoma ( )
Membranous glomerulonephritis ( )
Non-insulin dependent diabetes ( )
Non-small-cell lung cancer ( )
Parkinson disease ( )
Plasma cell myeloma ( )
UniProt ID
IF4A2_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
3BOR
EC Number
3.6.4.13
Pfam ID
PF00270 ; PF00271
Sequence
MSGGSADYNREHGGPEGMDPDGVIESNWNEIVDNFDDMNLKESLLRGIYAYGFEKPSAIQ
QRAIIPCIKGYDVIAQAQSGTGKTATFAISILQQLEIEFKETQALVLAPTRELAQQIQKV
ILALGDYMGATCHACIGGTNVRNEMQKLQAEAPHIVVGTPGRVFDMLNRRYLSPKWIKMF
VLDEADEMLSRGFKDQIYEIFQKLNTSIQVVLLSATMPTDVLEVTKKFMRDPIRILVKKE
ELTLEGIKQFYINVEREEWKLDTLCDLYETLTITQAVIFLNTRRKVDWLTEKMHARDFTV
SALHGDMDQKERDVIMREFRSGSSRVLITTDLLARGIDVQQVSLVINYDLPTNRENYIHR
IGRGGRFGRKGVAINFVTEEDKRILRDIETFYNTTVEEMPMNVADLI
Function
ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome. In the current model of translation initiation, eIF4A unwinds RNA secondary structures in the 5'-UTR of mRNAs which is necessary to allow efficient binding of the small ribosomal subunit, and subsequent scanning for the initiator codon.
Reactome Pathway
L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827 )
Deadenylation of mRNA (R-HSA-429947 )
Translation initiation complex formation (R-HSA-72649 )
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S (R-HSA-72662 )
Ribosomal scanning and start codon recognition (R-HSA-72702 )
GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706 )
M-decay (R-HSA-9820841 )
Z-decay (R-HSA-9820865 )
ISG15 antiviral mechanism (R-HSA-1169408 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Meningioma DISPT4TG Definitive Altered Expression [1]
T-cell acute lymphoblastic leukaemia DIS17AI2 Definitive Biomarker [2]
Triple negative breast cancer DISAMG6N Definitive Biomarker [3]
Adult lymphoma DISK8IZR Strong Biomarker [4]
Advanced cancer DISAT1Z9 Strong Biomarker [5]
Alzheimer disease DISF8S70 Strong Biomarker [6]
B-cell lymphoma DISIH1YQ Strong Altered Expression [4]
B-cell neoplasm DISVY326 Strong Biomarker [4]
Breast carcinoma DIS2UE88 Strong Altered Expression [3]
Chikungunya virus infection DISDXEHY Strong Biomarker [7]
Colonic neoplasm DISSZ04P Strong Biomarker [8]
Colorectal carcinoma DIS5PYL0 Strong Biomarker [9]
Colorectal neoplasm DISR1UCN Strong Altered Expression [9]
Cytomegalovirus infection DISCEMGC Strong Altered Expression [10]
Esophageal adenocarcinoma DISODWFP Strong Altered Expression [11]
Familial multiple trichoepithelioma DISKZAUY Strong Biomarker [11]
Herpes simplex infection DISL1SAV Strong Altered Expression [12]
Immunodeficiency DIS093I0 Strong Biomarker [8]
Leukemia DISNAKFL Strong Biomarker [13]
Lung cancer DISCM4YA Strong Biomarker [14]
Lung carcinoma DISTR26C Strong Biomarker [15]
Lymphoma DISN6V4S Strong Biomarker [4]
Lymphoma, non-Hodgkin, familial DISCXYIZ Strong Biomarker [16]
Malignant glioma DISFXKOV Strong Biomarker [17]
Malignant peripheral nerve sheath tumor DIS0JTN6 Strong Biomarker [18]
Matthew-Wood syndrome DISA7HR7 Strong Biomarker [19]
Medulloblastoma DISZD2ZL Strong Biomarker [20]
Mesothelioma DISKWK9M Strong Biomarker [21]
Metastatic malignant neoplasm DIS86UK6 Strong Biomarker [22]
Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures DIS51SK0 Strong Autosomal dominant [23]
Non-hodgkin lymphoma DISS2Y8A Strong Biomarker [16]
Pancreatic cancer DISJC981 Strong Biomarker [19]
Pediatric lymphoma DIS51BK2 Strong Biomarker [4]
Schizophrenia DISSRV2N Strong Altered Expression [24]
Carcinoma DISH9F1N moderate Altered Expression [25]
Influenza DIS3PNU3 moderate Biomarker [26]
Pancreatic ductal carcinoma DIS26F9Q Disputed Biomarker [27]
Patent ductus arteriosus DIS9P8YS Disputed Biomarker [27]
Breast cancer DIS7DPX1 Limited Altered Expression [3]
Melanoma DIS1RRCY Limited Altered Expression [28]
Membranous glomerulonephritis DISFSUKQ Limited Biomarker [29]
Non-insulin dependent diabetes DISK1O5Z Limited Biomarker [30]
Non-small-cell lung cancer DIS5Y6R9 Limited Biomarker [31]
Parkinson disease DISQVHKL Limited Genetic Variation [32]
Plasma cell myeloma DIS0DFZ0 Limited Altered Expression [33]
------------------------------------------------------------------------------------
⏷ Show the Full List of 45 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 2 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Temozolomide DMKECZD Approved Eukaryotic initiation factor 4A-II (EIF4A2) affects the response to substance of Temozolomide. [56]
DTI-015 DMXZRW0 Approved Eukaryotic initiation factor 4A-II (EIF4A2) affects the response to substance of DTI-015. [56]
------------------------------------------------------------------------------------
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the methylation of Eukaryotic initiation factor 4A-II (EIF4A2). [34]
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of Eukaryotic initiation factor 4A-II (EIF4A2). [40]
------------------------------------------------------------------------------------
23 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [35]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [36]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [37]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [38]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [39]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [41]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [42]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [43]
Demecolcine DMCZQGK Approved Demecolcine decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [44]
Niclosamide DMJAGXQ Approved Niclosamide increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [45]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [46]
Diclofenac DMPIHLS Approved Diclofenac affects the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [43]
Piroxicam DMTK234 Approved Piroxicam decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [47]
Resveratrol DM3RWXL Phase 3 Resveratrol decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [48]
Tamibarotene DM3G74J Phase 3 Tamibarotene decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [36]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [49]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [50]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [44]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [51]
chloropicrin DMSGBQA Investigative chloropicrin affects the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [52]
Acetaldehyde DMJFKG4 Investigative Acetaldehyde increases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [53]
Phencyclidine DMQBEYX Investigative Phencyclidine decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [54]
AHPN DM8G6O4 Investigative AHPN decreases the expression of Eukaryotic initiation factor 4A-II (EIF4A2). [55]
------------------------------------------------------------------------------------
⏷ Show the Full List of 23 Drug(s)

References

1 Validation of Reference Genes for Expression Studies in Human Meningiomas under Different Experimental Settings.Mol Neurobiol. 2018 Jul;55(7):5787-5797. doi: 10.1007/s12035-017-0800-3. Epub 2017 Oct 27.
2 RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.Nature. 2014 Sep 4;513(7516):65-70. doi: 10.1038/nature13485. Epub 2014 Jul 27.
3 The CXCR4-LASP1-eIF4F Axis Promotes Translation of Oncogenic Proteins in Triple-Negative Breast Cancer Cells.Front Oncol. 2019 Apr 24;9:284. doi: 10.3389/fonc.2019.00284. eCollection 2019.
4 Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase.Blood. 2014 Dec 11;124(25):3758-67. doi: 10.1182/blood-2014-07-589689. Epub 2014 Oct 15.
5 Translating from cancer to the brain: regulation of protein synthesis by eIF4F.Learn Mem. 2019 Aug 15;26(9):332-342. doi: 10.1101/lm.050047.119. Print 2019 Sep.
6 eIF4A inhibition allows translational regulation of mRNAs encoding proteins involved in Alzheimer's disease.PLoS One. 2010 Sep 28;5(9):e13030. doi: 10.1371/journal.pone.0013030.
7 Silvestrol Inhibits Chikungunya Virus Replication.Viruses. 2018 Oct 30;10(11):592. doi: 10.3390/v10110592.
8 STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A.Mol Cancer Ther. 2016 Dec;15(12):3055-3063. doi: 10.1158/1535-7163.MCT-16-0416.
9 Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer.J Exp Clin Cancer Res. 2019 May 14;38(1):196. doi: 10.1186/s13046-019-1178-z.
10 Differential role for host translation factors in host and viral protein synthesis during human cytomegalovirus infection.J Virol. 2014 Feb;88(3):1473-83. doi: 10.1128/JVI.02321-13. Epub 2013 Nov 6.
11 Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype.Cancer Gene Ther. 2012 Sep;19(9):609-18. doi: 10.1038/cgt.2012.39. Epub 2012 Jul 6.
12 Phosphorylation of eIF4E by Mnk-1 enhances HSV-1 translation and replication in quiescent cells.Genes Dev. 2004 Mar 15;18(6):660-72. doi: 10.1101/gad.1185304.
13 A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1.Open Biol. 2014 Nov;4(11):140180. doi: 10.1098/rsob.140180.
14 Targeting EIF4F complex in non-small cell lung cancer cells.Oncotarget. 2017 Jun 8;8(33):55731-55735. doi: 10.18632/oncotarget.18413. eCollection 2017 Aug 15.
15 Downregulation of EIF4A2 in non-small-cell lung cancer associates with poor prognosis.Clin Lung Cancer. 2013 Nov;14(6):658-65. doi: 10.1016/j.cllc.2013.04.011. Epub 2013 Jul 16.
16 Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma.Oncotarget. 2015 Apr 20;6(11):9488-501. doi: 10.18632/oncotarget.3378.
17 Inhibition of eIF4F complex loading inhibits the survival of malignant glioma.Oncol Rep. 2018 Oct;40(4):2399-2407. doi: 10.3892/or.2018.6587. Epub 2018 Jul 20.
18 Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas.Mol Cancer Ther. 2020 Mar;19(3):731-741. doi: 10.1158/1535-7163.MCT-19-0809. Epub 2019 Dec 17.
19 eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer.JCI Insight. 2019 Nov 1;4(21):e121951. doi: 10.1172/jci.insight.121951.
20 Proteomic analysis of Medulloblastoma reveals functional biology with translational potential.Acta Neuropathol Commun. 2018 Jun 7;6(1):48. doi: 10.1186/s40478-018-0548-7.
21 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma.Invest New Drugs. 2018 Apr;36(2):217-229. doi: 10.1007/s10637-017-0535-z. Epub 2017 Nov 8.
22 eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.Nature. 2014 Sep 4;513(7516):105-9. doi: 10.1038/nature13572. Epub 2014 Jul 27.
23 Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
24 Alterations in oligodendrocyte proteins, calcium homeostasis and new potential markers in schizophrenia anterior temporal lobe are revealed by shotgun proteome analysis.J Neural Transm (Vienna). 2009 Mar;116(3):275-89. doi: 10.1007/s00702-008-0156-y. Epub 2008 Nov 26.
25 Key contribution of eIF4H-mediated translational control in tumor promotion.Oncotarget. 2015 Nov 24;6(37):39924-40. doi: 10.18632/oncotarget.5442.
26 Functional impairment of eIF4A and eIF4G factors correlates with inhibition of influenza virus mRNA translation.Virology. 2011 Apr 25;413(1):93-102. doi: 10.1016/j.virol.2011.02.012. Epub 2011 Mar 5.
27 eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma.Nat Commun. 2019 Nov 13;10(1):5151. doi: 10.1038/s41467-019-13086-5.
28 Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma.Nat Med. 2018 Dec;24(12):1877-1886. doi: 10.1038/s41591-018-0217-1. Epub 2018 Oct 29.
29 Biomarker prediction for membranous nephropathy prognosis by microarray analysis.Nephrology (Carlton). 2019 May;24(5):526-533. doi: 10.1111/nep.13446.
30 EIF4A2 is a positional candidate gene at the 3q27 locus linked to type 2 diabetes in French families.Diabetes. 2006 Apr;55(4):1171-6. doi: 10.2337/diabetes.55.04.06.db05-1298.
31 Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer.Cancer Gene Ther. 2019 May;26(5-6):157-165. doi: 10.1038/s41417-018-0058-6. Epub 2018 Nov 12.
32 EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?.Neurobiol Aging. 2012 Sep;33(9):2233.e1-2233.e5. doi: 10.1016/j.neurobiolaging.2012.05.006. Epub 2012 Jun 1.
33 eIF4E and eIF4GI have distinct and differential imprints on multiple myeloma's proteome and signaling.Oncotarget. 2015 Feb 28;6(6):4315-29. doi: 10.18632/oncotarget.3008.
34 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.
35 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
36 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
37 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.
38 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
39 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.
40 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.
41 Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
42 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
43 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.
44 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
45 Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
46 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.
47 Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
48 Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
49 Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
50 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.
51 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
52 Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
53 In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
54 Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
55 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.
56 Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.