Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX5W77I)

• DOT Name: Antizyme inhibitor 1 (AZIN1)
• Synonyms: AZI; AZI1; Ornithine decarboxylase antizyme inhibitor
• Gene Name: AZIN1
• Related Disease:
  Bardet biedl syndrome
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Diabetic kidney disease
  Esophageal squamous cell carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Liver cirrhosis
  Lung cancer
  Male infertility
  Neoplasm
  Non-small-cell lung cancer
  Pneumocystis pneumonia
  Prostate neoplasm
  Advanced cancer
  Gastric cancer
  Stomach cancer
• UniProt ID: AZIN1_HUMAN
• PDB ID: 4ZGZ
• Pfam ID: PF02784 ; PF00278
• Sequence:
  MKGFIDDANYSVGLLDEGTNLGNVIDNYVYEHTLTGKNAFFVGDLGKIVKKHSQWQNVVA
  QIKPFYTVKCNSAPAVLEILAALGTGFACSSKNEMALVQELGVPPENIIYISPCKQVSQI
  KYAAKVGVNILTCDNEIELKKIARNHPNAKVLLHIATEDNIGGEEGNMKFGTTLKNCRHL
  LECAKELDVQIIGVKFHVSSACKESQVYVHALSDARCVFDMAGEIGFTMNMLDIGGGFTG
  TEFQLEEVNHVISPLLDIYFPEGSGVKIISEPGSYYVSSAFTLAVNIIAKKVVENDKFPS
  GVEKTGSDEPAFMYYMNDGVYGSFASKLSEDLNTIPEVHKKYKEDEPLFTSSLWGPSCDE
  LDQIVESCLLPELNVGDWLIFDNMGADSFHEPSAFNDFQRPAIYYMMSFSDWYEMQDAGI
  TSDSMMKNFFFVPSCIQLSQEDSFSAEA
• Function: Antizyme inhibitor (AZI) protein that positively regulates ornithine decarboxylase (ODC) activity and polyamine uptake. AZI is an enzymatically inactive ODC homolog that counteracts the negative effect of ODC antizymes (AZs) OAZ1, OAZ2 and OAZ3 on ODC activity by competing with ODC for antizyme-binding. Inhibits antizyme-dependent ODC degradation and releases ODC monomers from their inactive complex with antizymes, leading to formation of the catalytically active ODC homodimer and restoring polyamine production.
• Tissue Specificity: Expressed in liver.
• Reactome Pathway: Regulation of ornithine decarboxylase (ODC) (R-HSA-350562)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Diabetic kidney disease	DISJMWEY	Strong	Therapeutic	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Male infertility	DISY3YZZ	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Pneumocystis pneumonia	DISFSOM3	Strong	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[13]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[14]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[15]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Antizyme inhibitor 1 (AZIN1).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Antizyme inhibitor 1 (AZIN1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Antizyme inhibitor 1 (AZIN1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Antizyme inhibitor 1 (AZIN1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Antizyme inhibitor 1 (AZIN1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Antizyme inhibitor 1 (AZIN1).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Antizyme inhibitor 1 (AZIN1).	[22]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Antizyme inhibitor 1 (AZIN1).	[23]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Antizyme inhibitor 1 (AZIN1).	[22]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Antizyme inhibitor 1 (AZIN1).	[18]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Antizyme inhibitor 1 (AZIN1).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Antizyme inhibitor 1 (AZIN1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Antizyme inhibitor 1 (AZIN1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Antizyme inhibitor 1 (AZIN1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Antizyme inhibitor 1 (AZIN1).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Antizyme inhibitor 1 (AZIN1).	[29]

References

• [1] The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome.PLoS Genet. 2014 Feb 13;10(2):e1004083. doi: 10.1371/journal.pgen.1004083. eCollection 2014 Feb.
• [2] Single-Cell Transcriptome Analysis Reveals Estrogen Signaling Coordinately Augments One-Carbon, Polyamine, and Purine Synthesis in Breast Cancer.Cell Rep. 2018 Nov 20;25(8):2285-2298.e4. doi: 10.1016/j.celrep.2018.10.093.
• [3] Ornithine decarboxylase antizyme inhibitor 2 (AZIN2) is a signature of secretory phenotype and independent predictor of adverse prognosis in colorectal cancer.PLoS One. 2019 Feb 15;14(2):e0211564. doi: 10.1371/journal.pone.0211564. eCollection 2019.
• [4] Pancreatic Kininogenase Ameliorates Renal Fibrosis in Streptozotocin Induced-Diabetic Nephropathy Rat.Kidney Blood Press Res. 2016;41(1):9-17. doi: 10.1159/000368542. Epub 2016 Jan 8.
• [5] Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma.Cancer Res. 2014 Feb 1;74(3):840-51. doi: 10.1158/0008-5472.CAN-13-2545. Epub 2013 Dec 3.
• [6] A polymorphism that delays fibrosis in hepatitis C promotes alternative splicing of AZIN1, reducing fibrogenesis.Hepatology. 2011 Dec;54(6):2198-207. doi: 10.1002/hep.24608.
• [7] Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma.Nat Med. 2013 Feb;19(2):209-16. doi: 10.1038/nm.3043. Epub 2013 Jan 6.
• [8] A candidate gene study for the association of host single nucleotide polymorphisms with liver cirrhosis risk in chinese hepatitis B patients.Genet Test Mol Biomarkers. 2013 Sep;17(9):681-6. doi: 10.1089/gtmb.2013.0058. Epub 2013 Jul 11.
• [9] RNA editing of AZIN1 induces the malignant progression of non-small-cell lung cancers.Tumour Biol. 2017 Aug;39(8):1010428317700001. doi: 10.1177/1010428317700001.
• [10] Acute versus chronic loss of mammalian Azi1/Cep131 results in distinct ciliary phenotypes.PLoS Genet. 2013;9(12):e1003928. doi: 10.1371/journal.pgen.1003928. Epub 2013 Dec 26.
• [11] Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer.Cancer Lett. 2019 Mar 1;444:127-135. doi: 10.1016/j.canlet.2018.12.009. Epub 2018 Dec 21.
• [12] Pneumocystis mediates overexpression of antizyme inhibitor resulting in increased polyamine levels and apoptosis in alveolar macrophages.J Biol Chem. 2009 Mar 20;284(12):8174-84. doi: 10.1074/jbc.M805787200. Epub 2009 Jan 20.
• [13] Knockdown of antizyme inhibitor decreases prostate tumor growth in vivo.Amino Acids. 2012 Feb;42(2-3):549-58. doi: 10.1007/s00726-011-1032-x. Epub 2011 Sep 11.
• [14] AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer.JCI Insight. 2018 Jun 21;3(12):e99976. doi: 10.1172/jci.insight.99976. eCollection 2018 Jun 21.
• [15] Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer.J Transl Med. 2018 Dec 18;16(1):366. doi: 10.1186/s12967-018-1740-z.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [22] 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.
• [23] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [24] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [25] 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.
• [26] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
• [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] Unique bisphenol A transcriptome in prostate cancer: novel effects on ERbeta expression that correspond to androgen receptor mutation status. Environ Health Perspect. 2007 Nov;115(11):1646-53. doi: 10.1289/ehp.10283.
• [29] 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.