Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4CIWLJ)

• DOT Name: Syntaxin-3 (STX3)
• Gene Name: STX3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Diarrhea
  Intestinal disorder
  Neoplasm
  Retinal dystrophy and microvillus inclusion disease
  Microvillus inclusion disease
  Intellectual disability
• UniProt ID: STX3_HUMAN
• Pfam ID: PF05739 ; PF00804
• Sequence:
  MKDRLEQLKAKQLTQDDDTDAVEIAIDNTAFMDEFFSEIEETRLNIDKISEHVEEAKKLY
  SIILSAPIPEPKTKDDLEQLTTEIKKRANNVRNKLKSMEKHIEEDEVRSSADLRIRKSQH
  SVLSRKFVEVMTKYNEAQVDFRERSKGRIQRQLEITGKKTTDEELEEMLESGNPAIFTSG
  IIDSQISKQALSEIEGRHKDIVRLESSIKELHDMFMDIAMLVENQGEMLDNIELNVMHTV
  DHVEKARDETKKAVKYQSQARKKLIIIIVLVVVLLGILALIIGLSVGLN
• Function: Potentially involved in docking of synaptic vesicles at presynaptic active zones. Apical receptor involved in membrane fusion of apical vesicles; [Isoform B]: Essential for survival of retinal photoreceetors; [Isoform 3]: Functions as a regulator of gene expression.
• Tissue Specificity: .Expressed in small intestine, kidney, pancreas, placenta as well as in retina. Weaker expression in lung, liver and heart. Not expressed in brain and skeletal muscle.; [Isoform B]: Expressed only in the retina.; [Isoform 3]: Ubiquitously expressed.
• KEGG Pathway:
  S.RE interactions in vesicular transport (hsa04130)
  Sy.ptic vesicle cycle (hsa04721)
• Reactome Pathway: Other interleukin signaling (R-HSA-449836)

Molecular Interaction Atlas (MIA) of This DOT

8 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]
Diarrhea	DISWTJQL	Strong	Genetic Variation	[2]
Intestinal disorder	DISGPMUQ	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Retinal dystrophy and microvillus inclusion disease	DIS0OGW4	Strong	Autosomal recessive	[4]
Microvillus inclusion disease	DIS6L4RW	Moderate	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Syntaxin-3 (STX3) decreases the response to substance of Doxorubicin.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Syntaxin-3 (STX3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Syntaxin-3 (STX3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Syntaxin-3 (STX3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Syntaxin-3 (STX3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Syntaxin-3 (STX3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Syntaxin-3 (STX3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Syntaxin-3 (STX3).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Syntaxin-3 (STX3).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Syntaxin-3 (STX3).	[16]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Syntaxin-3 (STX3).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Syntaxin-3 (STX3).	[18]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Syntaxin-3 (STX3).	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Syntaxin-3 (STX3).	[20]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Syntaxin-3 (STX3).	[21]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Syntaxin-3 (STX3).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Syntaxin-3 (STX3).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Syntaxin-3 (STX3).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Syntaxin-3 (STX3).	[25]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Syntaxin-3 (STX3).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Syntaxin-3 (STX3).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Syntaxin-3 (STX3).	[28]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Syntaxin-3 (STX3).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Syntaxin-3 (STX3).	[13]

References

• [1] STX3 represses the stability of the tumor suppressor PTEN to activate the PI3K-Akt-mTOR signaling and promotes the growth of breast cancer cells.Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1684-1692. doi: 10.1016/j.bbadis.2018.01.031. Epub 2018 Feb 2.
• [2] MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update.Hum Mutat. 2018 Mar;39(3):333-344. doi: 10.1002/humu.23386. Epub 2018 Jan 17.
• [3] Disruption of Rab8a and Rab11a causes formation of basolateral microvilli in neonatal enteropathy.J Cell Sci. 2017 Aug 1;130(15):2491-2505. doi: 10.1242/jcs.201897. Epub 2017 Jun 8.
• [4] Loss of syntaxin 3 causes variant microvillus inclusion disease. Gastroenterology. 2014 Jul;147(1):65-68.e10. doi: 10.1053/j.gastro.2014.04.002. Epub 2014 Apr 12.
• [5] 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.
• [6] Autosomal recessive congenital cataract, intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family.Clin Genet. 2015 Sep;88(3):283-7. doi: 10.1111/cge.12489. Epub 2014 Oct 30.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [17] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] 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.
• [20] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [21] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [22] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [27] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [30] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.