Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDT0XZK)

• DOT Name: Apoptosis regulatory protein Siva (SIVA1)
• Synonyms: CD27-binding protein; CD27BP
• Gene Name: SIVA1
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Pneumonia
  Colon cancer
  Colon carcinoma
  Coxsackie virus infection
  Lung adenocarcinoma
  Neoplasm
  Nasopharyngeal carcinoma
  Retinopathy
  Advanced cancer
  Bone osteosarcoma
  Hepatocellular carcinoma
  Non-small-cell lung cancer
  Osteosarcoma
• UniProt ID: SIVA_HUMAN
• Pfam ID: PF05458
• Sequence:
  MPKRSCPFADVAPLQLKVRVSQRELSRGVCAERYSQEVFEKTKRLLFLGAQAYLDHVWDE
  GCAVVHLPESPKPGPTGAPRAARGQMLIGPDGRLIRSLGQASEADPSGVASIACSSCVRA
  VDGKAVCGQCERALCGQCVRTCWGCGSVACTLCGLVDCSDMYEKVLCTSCAMFET
• Function: Induces CD27-mediated apoptosis. Inhibits BCL2L1 isoform Bcl-x(L) anti-apoptotic activity. Inhibits activation of NF-kappa-B and promotes T-cell receptor-mediated apoptosis.
• Tissue Specificity: Ubiquitous. Mostly expressed in thymus, testis, ovary, prostate, small intestine and spleen and less in colon.
• KEGG Pathway: p53 sig.ling pathway (hsa04115)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Altered Expression	[1]
Liver cancer	DISDE4BI	Definitive	Altered Expression	[1]
Pneumonia	DIS8EF3M	Definitive	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Coxsackie virus infection	DISY1VPA	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[7]
Retinopathy	DISB4B0F	moderate	Biomarker	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[6]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[9]

19 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 Apoptosis regulatory protein Siva (SIVA1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Apoptosis regulatory protein Siva (SIVA1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Apoptosis regulatory protein Siva (SIVA1).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Apoptosis regulatory protein Siva (SIVA1).	[18]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[19]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[20]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[21]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[22]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Apoptosis regulatory protein Siva (SIVA1).	[15]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Apoptosis regulatory protein Siva (SIVA1).	[15]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Apoptosis regulatory protein Siva (SIVA1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Apoptosis regulatory protein Siva (SIVA1).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Apoptosis regulatory protein Siva (SIVA1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Apoptosis regulatory protein Siva (SIVA1).	[16]

References

• [1] Plumbagin inhibits proliferation and induces apoptosis of hepatocellular carcinoma by downregulating the expression of SIVA.Drug Des Devel Ther. 2019 Apr 23;13:1289-1300. doi: 10.2147/DDDT.S200610. eCollection 2019.
• [2] Scheduled Intravenous Acetaminophen for Postoperative Management of Patients Who Had Thoracoscopic Esophagectomy for Esophageal Cancer.Anticancer Res. 2019 Jan;39(1):467-470. doi: 10.21873/anticanres.13135.
• [3] Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1.Apoptosis. 2011 Jan;16(1):35-44. doi: 10.1007/s10495-010-0538-0.
• [4] The zinc containing pro-apoptotic protein siva interacts with the peroxisomal membrane protein pmp22.Mol Cell Biochem. 2006 Jul;287(1-2):147-55. doi: 10.1007/s11010-005-9082-6. Epub 2006 May 9.
• [5] Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma.Mol Carcinog. 2009 Dec;48(12):1116-22. doi: 10.1002/mc.20563.
• [6] Siva-1 emerges as a tissue-specific oncogene beyond its classic role of a proapoptotic gene.Onco Targets Ther. 2018 Oct 1;11:6361-6367. doi: 10.2147/OTT.S173001. eCollection 2018.
• [7] Anticancer activity of recombinant Siva1 protein in human nasopharyngeal carcinoma cell line CNE-2.Cancer Biomark. 2015;15(6):833-41. doi: 10.3233/CBM-150527.
• [8] Retinal Vascular Imaging Markers and Incident Chronic Kidney Disease: A Prospective Cohort Study.Sci Rep. 2017 Aug 24;7(1):9374. doi: 10.1038/s41598-017-09204-2.
• [9] Siva 1 inhibits proliferation, migration and invasion by phosphorylating Stathmin in ovarian cancer cells.Oncol Lett. 2017 Aug;14(2):1512-1518. doi: 10.3892/ol.2017.6307. Epub 2017 Jun 2.
• [10] Overexpression of miR-664 is associated with poor overall survival and accelerates cell proliferation, migration and invasion in hepatocellular carcinoma.Onco Targets Ther. 2019 Mar 28;12:2373-2381. doi: 10.2147/OTT.S188658. eCollection 2019.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] 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.
• [19] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [20] Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
• [21] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [22] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.