Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR8RF9X)

• DOT Name: Eukaryotic translation initiation factor 3 subunit C (EIF3C)
• Synonyms: eIF3c; Eukaryotic translation initiation factor 3 subunit 8; eIF3 p110
• Gene Name: EIF3C
• Related Disease:
  Autoimmune disease
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Glioma
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Renal cell carcinoma
  Systemic lupus erythematosus
  Advanced cancer
  Neurofibromatosis type 2
• UniProt ID: EIF3C_HUMAN
• PDB ID: 3J8B; 3J8C; 6YBD; 6YBW; 6ZMW; 6ZON; 6ZP4; 7A09; 7QP6; 7QP7; 8PPL
• Pfam ID: PF05470 ; PF01399
• Sequence:
  MSRFFTTGSDSESESSLSGEELVTKPVGGNYGKQPLLLSEDEEDTKRVVRSAKDKRFEEL
  TNLIRTIRNAMKIRDVTKCLEEFELLGKAYGKAKSIVDKEGVPRFYIRILADLEDYLNEL
  WEDKEGKKKMNKNNAKALSTLRQKIRKYNRDFESHITSYKQNPEQSADEDAEKNEEDSEG
  SSDEDEDEDGVSAATFLKKKSEAPSGESRKFLKKMDDEDEDSEDSEDDEDWDTGSTSSDS
  DSEEEEGKQTALASRFLKKAPTTDEDKKAAEKKREDKAKKKHDRKSKRLDEEEEDNEGGE
  WERVRGGVPLVKEKPKMFAKGTEITHAVVIKKLNEILQARGKKGTDRAAQIELLQLLVQI
  AAENNLGEGVIVKIKFNIIASLYDYNPNLATYMKPEMWGKCLDCINELMDILFANPNIFV
  GENILEESENLHNADQPLRVRGCILTLVERMDEEFTKIMQNTDPHSQEYVEHLKDEAQVC
  AIIERVQRYLEEKGTTEEVCRIYLLRILHTYYKFDYKAHQRQLTPPEGSSKSEQDQAENE
  GEDSAVLMERLCKYIYAKDRTDRIRTCAILCHIYHHALHSRWYQARDLMLMSHLQDNIQH
  ADPPVQILYNRTMVQLGICAFRQGLTKDAHNALLDIQSSGRAKELLGQGLLLRSLQERNQ
  EQEKVERRRQVPFHLHINLELLECVYLVSAMLLEIPYMAAHESDARRRMISKQFHHQLRV
  GERQPLLGPPESMREHVVAASKAMKMGDWKTCHSFIINEKMNGKVWDLFPEADKVRTMLV
  RKIQEESLRTYLFTYSSVYDSISMETLSDMFELDLPTVHSIISKMIINEELMASLDQPTQ
  TVVMHRTEPTAQQNLALQLAEKLGSLVENNERVFDHKQGTYGGYFRDQKDGYRKNEGYMR
  RGGYRQQQSQTAY
• 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

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[6]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[4]
Neurofibromatosis type 2	DISI8ECS	Limited	Biomarker	[10]

16 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 Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[17]
Selenium	DM25CGV	Approved	Selenium increases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[19]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[17]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[14]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[14]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[14]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[20]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Eukaryotic translation initiation factor 3 subunit C (EIF3C).	[22]

References

• [1] Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus.Mol Immunol. 2006 Mar;43(9):1497-507. doi: 10.1016/j.molimm.2005.07.039. Epub 2005 Sep 6.
• [2] Knockdown of EIF3C promotes human U-2OS cells apoptosis through increased CASP3/7 and Chk1/2 by upregulating SAPK/JNK.Onco Targets Ther. 2019 Feb 14;12:1225-1235. doi: 10.2147/OTT.S187209. eCollection 2019.
• [3] Decreasing Eukaryotic Initiation Factor 3C (EIF3C) Suppresses Proliferation and Stimulates Apoptosis in Breast Cancer Cell Lines Through Mammalian Target of Rapamycin (mTOR) Pathway.Med Sci Monit. 2017 Aug 30;23:4182-4191. doi: 10.12659/msm.906389.
• [4] Upregulated expression of eIF3C is associated with malignant behavior in renal cell carcinoma.Int J Oncol. 2019 Dec;55(6):1385-1395. doi: 10.3892/ijo.2019.4903. Epub 2019 Oct 21.
• [5] Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells.J Zhejiang Univ Sci B. 2013 Jun;14(6):451-9. doi: 10.1631/jzus.B1200230.
• [6] 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.
• [7] Eukaryotic initiation factor 3C silencing inhibits cell proliferation and promotes apoptosis in human glioma.Oncol Rep. 2015 Jun;33(6):2954-62. doi: 10.3892/or.2015.3881. Epub 2015 Mar 30.
• [8] EIF3C-enhanced exosome secretion promotes angiogenesis and tumorigenesis of human hepatocellular carcinoma.Oncotarget. 2018 Jan 11;9(17):13193-13205. doi: 10.18632/oncotarget.24149. eCollection 2018 Mar 2.
• [9] Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer.Oncotarget. 2018 Dec 25;9(101):37520-37533. doi: 10.18632/oncotarget.26494. eCollection 2018 Dec 25.
• [10] Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c).Hum Mol Genet. 2006 Apr 1;15(7):1059-70. doi: 10.1093/hmg/ddl021. Epub 2006 Feb 23.
• [11] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [12] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [13] 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.
• [14] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [21] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [22] 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.
• [23] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.