Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD4NOYS)

• DOT Name: Etoposide-induced protein 2.4 homolog (EI24)
• Synonyms: p53-induced gene 8 protein
• Gene Name: EI24
• Related Disease:
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Epithelial neoplasm
  Esophageal squamous cell carcinoma
  Non-small-cell lung cancer
  Pancreatic tumour
  Prostate cancer
  Prostate neoplasm
  Retinoblastoma
  Skin cancer
  Triple negative breast cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Lung cancer
  Lung carcinoma
  Advanced cancer
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Type-1/2 diabetes
• UniProt ID: EI24_HUMAN
• Pfam ID: PF07264
• Sequence:
  MADSVKTFLQDLARGIKDSIWGICTISKLDARIQQKREEQRRRRASSVLAQRRAQSIERK
  QESEPRIVSRIFQCCAWNGGVFWFSLLLFYRVFIPVLQSVTARIIGDPSLHGDVWSWLEF
  FLTSIFSALWVLPLFVLSKVVNAIWFQDIADLAFEVSGRKPHPFPSVSKIIADMLFNLLL
  QALFLIQGMFVSLFPIHLVGQLVSLLHMSLLYSLYCFEYRWFNKGIEMHQRLSNIERNWP
  YYFGFGLPLAFLTAMQSSYIISGCLFSILFPLFIISANEAKTPGKAYLFQLRLFSLVVFL
  SNRLFHKTVYLQSALSSSTSAEKFPSPHPSPAKLKATAGH
• Function: Acts as a negative growth regulator via p53-mediated apoptosis pathway. Regulates formation of degradative autolysosomes during autophagy.
• KEGG Pathway: p53 sig.ling pathway (hsa04115)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[8]
Skin cancer	DISTM18U	Strong	Biomarker	[1]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[9]
Cervical carcinoma	DIST4S00	moderate	Posttranslational Modification	[10]
Cervical Intraepithelial neoplasia	DISXP757	moderate	Genetic Variation	[10]
Lung cancer	DISCM4YA	moderate	Altered Expression	[11]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[11]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[5]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[12]
Pancreatic cancer	DISJC981	Limited	Biomarker	[12]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[13]

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 Etoposide-induced protein 2.4 homolog (EI24).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Etoposide-induced protein 2.4 homolog (EI24).	[28]

19 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 Etoposide-induced protein 2.4 homolog (EI24).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[20]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[22]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[23]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[24]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[23]
Amifostine	DM5FL14	Approved	Amifostine decreases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[26]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[27]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[30]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[31]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of Etoposide-induced protein 2.4 homolog (EI24).	[32]

References

• [1] Ei24-deficiency attenuates protein kinase C signaling and skin carcinogenesis in mice.Int J Biochem Cell Biol. 2012 Nov;44(11):1887-96. doi: 10.1016/j.biocel.2012.06.034. Epub 2012 Jul 6.
• [2] Effect of EI24 expression on the tumorigenesis of Apc(Min/+) colorectal cancer mouse model.Biochem Biophys Res Commun. 2019 Jul 5;514(4):1087-1092. doi: 10.1016/j.bbrc.2019.04.186. Epub 2019 May 13.
• [3] EI24 regulates epithelial-to-mesenchymal transition and tumor progression by suppressing TRAF2-mediated NF-B activity.Oncotarget. 2013 Dec;4(12):2383-96. doi: 10.18632/oncotarget.1434.
• [4] miR-483-3p plays an oncogenic role in esophageal squamous cell carcinoma by targeting tumor suppressor EI24.Cell Biol Int. 2016 Apr;40(4):448-55. doi: 10.1002/cbin.10585. Epub 2016 Feb 4.
• [5] Integrated analysis of the prognostic value of TP53 dependent etoposide-induced gene 24 in non-small cell lung cancer.Biomed Pharmacother. 2019 Apr;112:108590. doi: 10.1016/j.biopha.2019.01.051. Epub 2019 Feb 19.
• [6] EI24, as a Component of Autophagy, Is Involved in Pancreatic Cell Proliferation.Front Oncol. 2019 Jul 23;9:652. doi: 10.3389/fonc.2019.00652. eCollection 2019.
• [7] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [8] Ei24, a novel E2F target gene, affects p53-independent cell death upon ultraviolet C irradiation.J Biol Chem. 2013 Oct 25;288(43):31261-7. doi: 10.1074/jbc.M113.477570. Epub 2013 Sep 6.
• [9] MicroRNA-455-3p promotes invasion and migration in triple negative breast cancer by targeting tumor suppressor EI24.Oncotarget. 2017 Mar 21;8(12):19455-19466. doi: 10.18632/oncotarget.14307.
• [10] Inactivation of CHEK1 and EI24 is associated with the development of invasive cervical carcinoma: clinical and prognostic implications.Int J Cancer. 2011 Oct 15;129(8):1859-71. doi: 10.1002/ijc.25849. Epub 2011 Apr 1.
• [11] Reduced expression of EI24 confers resistance to gefitinib through IGF-1R signaling in PC9 NSCLC cells.Lung Cancer. 2015 Nov;90(2):175-81. doi: 10.1016/j.lungcan.2015.08.019. Epub 2015 Sep 3.
• [12] EI24 Suppresses Tumorigenesis in Pancreatic Cancer via Regulating c-Myc.Gastroenterol Res Pract. 2018 Oct 2;2018:2626545. doi: 10.1155/2018/2626545. eCollection 2018.
• [13] Etoposide-induced protein 2.4 functions as a regulator of the calcium ATPase and protects pancreatic -cell survival.J Biol Chem. 2018 Jun 29;293(26):10128-10140. doi: 10.1074/jbc.RA118.002399. Epub 2018 May 16.
• [14] 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.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] 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.
• [21] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [22] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [23] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [24] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [25] Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells. Mol Cancer Ther. 2003 Sep;2(9):893-900.
• [26] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [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] 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.
• [29] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [32] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.