Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBXAT3Z)

• DOT Name: Cytohesin-3 (CYTH3)
• Synonyms: ARF nucleotide-binding site opener 3; Protein ARNO3; General receptor of phosphoinositides 1; Grp1; PH, SEC7 and coiled-coil domain-containing protein 3
• Gene Name: CYTH3
• Related Disease:
  Breast neoplasm
  Cardiac failure
  Hepatocellular carcinoma
  Neoplasm
• UniProt ID: CYH3_HUMAN
• PDB ID: 4KAX; 6U3E; 6U3G
• Pfam ID: PF00169 ; PF01369
• Sequence:
  MDEDGGGEGGGVPEDLSLEEREELLDIRRRKKELIDDIERLKYEIAEVMTEIDNLTSVEE
  SKTTQRNKQIAMGRKKFNMDPKKGIQFLIENDLLQSSPEDVAQFLYKGEGLNKTVIGDYL
  GERDEFNIKVLQAFVELHEFADLNLVQALRQFLWSFRLPGEAQKIDRMMEAFASRYCLCN
  PGVFQSTDTCYVLSFAIIMLNTSLHNHNVRDKPTAERFIAMNRGINEGGDLPEELLRNLY
  ESIKNEPFKIPEDDGNDLTHTFFNPDREGWLLKLGGGRVKTWKRRWFILTDNCLYYFEYT
  TDKEPRGIIPLENLSIREVEDPRKPNCFELYNPSHKGQVIKACKTEADGRVVEGNHVVYR
  ISAPSPEEKEEWMKSIKASISRDPFYDMLATRKRRIANKK
• Function: Promotes guanine-nucleotide exchange on ARF1 and ARF6. Promotes the activation of ARF factors through replacement of GDP with GTP. Plays a role in the epithelial polarization.
• Tissue Specificity: Almost absent from liver, thymus and peripheral blood lymphocytes.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
• Reactome Pathway: Intra-Golgi traffic (R-HSA-6811438)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]

16 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 Cytohesin-3 (CYTH3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytohesin-3 (CYTH3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytohesin-3 (CYTH3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytohesin-3 (CYTH3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cytohesin-3 (CYTH3).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cytohesin-3 (CYTH3).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cytohesin-3 (CYTH3).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Cytohesin-3 (CYTH3).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cytohesin-3 (CYTH3).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cytohesin-3 (CYTH3).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Cytohesin-3 (CYTH3).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cytohesin-3 (CYTH3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cytohesin-3 (CYTH3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytohesin-3 (CYTH3).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cytohesin-3 (CYTH3).	[17]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Cytohesin-3 (CYTH3).	[18]

References

• [1] The lncRNA H19 mediates breast cancer cell plasticity during EMT and MET plasticity by differentially sponging miR-200b/c and let-7b.Sci Signal. 2017 Jun 13;10(483):eaak9557. doi: 10.1126/scisignal.aak9557.
• [2] Genetics of heart rate in heart failure patients (GenHRate).Hum Genomics. 2019 May 21;13(1):22. doi: 10.1186/s40246-019-0206-6.
• [3] Cytohesin-3 is upregulated in hepatocellular carcinoma and contributes to tumor growth and vascular invasion.Int J Clin Exp Pathol. 2014 Apr 15;7(5):2123-32. eCollection 2014.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] 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.
• [11] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] 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.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.