Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ7VLTP)

• DOT Name: Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15)
• Synonyms: ADAM 15; EC 3.4.24.-; Metalloprotease RGD disintegrin protein; Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 15; MDC-15; Metargidin
• Gene Name: ADAM15
• Related Disease:
  Colorectal carcinoma
  Ovarian neoplasm
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Bladder cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Chondrosarcoma
  Inflammatory bowel disease
  Metastatic prostate carcinoma
  Non-small-cell lung cancer
  Osteoarthritis
  Pancreatic cancer
  Prostate neoplasm
  Rheumatoid arthritis
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Bloom syndrome
  Breast cancer
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Prostate cancer
  Prostate carcinoma
  Adenocarcinoma
  Melanoma
  Neoplasm
  Systemic lupus erythematosus
• UniProt ID: ADA15_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF08516 ; PF00200 ; PF01562 ; PF01421
• Sequence:
  MRLALLWALGLLGAGSPLPSWPLPNIGGTEEQQAESEKAPREPLEPQVLQDDLPISLKKV
  LQTSLPEPLRIKLELDGDSHILELLQNRELVPGRPTLVWYQPDGTRVVSEGHTLENCCYQ
  GRVRGYAGSWVSICTCSGLRGLVVLTPERSYTLEQGPGDLQGPPIISRIQDLHLPGHTCA
  LSWRESVHTQKPPEHPLGQRHIRRRRDVVTETKTVELVIVADHSEAQKYRDFQHLLNRTL
  EVALLLDTFFRPLNVRVALVGLEAWTQRDLVEISPNPAVTLENFLHWRRAHLLPRLPHDS
  AQLVTGTSFSGPTVGMAIQNSICSPDFSGGVNMDHSTSILGVASSIAHELGHSLGLDHDL
  PGNSCPCPGPAPAKTCIMEASTDFLPGLNFSNCSRRALEKALLDGMGSCLFERLPSLPPM
  AAFCGNMFVEPGEQCDCGFLDDCVDPCCDSLTCQLRPGAQCASDGPCCQNCQLRPSGWQC
  RPTRGDCDLPEFCPGDSSQCPPDVSLGDGEPCAGGQAVCMHGRCASYAQQCQSLWGPGAQ
  PAAPLCLQTANTRGNAFGSCGRNPSGSYVSCTPRDAICGQLQCQTGRTQPLLGSIRDLLW
  ETIDVNGTELNCSWVHLDLGSDVAQPLLTLPGTACGPGLVCIDHRCQRVDLLGAQECRSK
  CHGHGVCDSNRHCYCEEGWAPPDCTTQLKATSSLTTGLLLSLLVLLVLVMLGASYWYRAR
  LHQRLCQLKGPTCQYRAAQSGPSERPGPPQRALLARGTKQASALSFPAPPSRPLPPDPVS
  KRLQAELADRPNPPTRPLPADPVVRSPKSQGPAKPPPPRKPLPADPQGRCPSGDLPGPGA
  GIPPLVVPSRPAPPPPTVSSLYL
• Function: Active metalloproteinase with gelatinolytic and collagenolytic activity. Plays a role in the wound healing process. Mediates both heterotypic intraepithelial cell/T-cell interactions and homotypic T-cell aggregation. Inhibits beta-1 integrin-mediated cell adhesion and migration of airway smooth muscle cells. Suppresses cell motility on or towards fibronectin possibly by driving alpha-v/beta-1 integrin (ITAGV-ITGB1) cell surface expression via ERK1/2 inactivation. Cleaves E-cadherin in response to growth factor deprivation. Plays a role in glomerular cell migration. Plays a role in pathological neovascularization. May play a role in cartilage remodeling. May be proteolytically processed, during sperm epididymal maturation and the acrosome reaction. May play a role in sperm-egg binding through its disintegrin domain.
• Tissue Specificity: Expressed in colon and small intestine. Expressed in airway smooth muscle and glomerular mesangial cells (at protein level). Ubiquitously expressed. Overexpressed in atherosclerotic lesions. Constitutively expressed in cultured endothelium and smooth muscle. Expressed in chondrocytes. Expressed in airway smooth muscle and glomerular mesangial cells.
• Reactome Pathway:
  Invadopodia formation (R-HSA-8941237)
  Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Altered Expression	[1]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Carcinoma	DISH9F1N	Strong	Altered Expression	[1]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[8]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[1]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Osteoarthritis	DIS05URM	Strong	Biomarker	[11]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[12]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[14]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Bloom syndrome	DISKXQ7J	moderate	Biomarker	[15]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[6]
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[16]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[16]
Prostate cancer	DISF190Y	moderate	Altered Expression	[17]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[17]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[18]
Melanoma	DIS1RRCY	Limited	Biomarker	[19]
Neoplasm	DISZKGEW	Limited	Biomarker	[17]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[26]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[27]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[28]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[29]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Disintegrin and metalloproteinase domain-containing protein 15 (ADAM15).	[24]

References

• [1] ADAM15 to 51 integrin switch in colon carcinoma cells: a late event in cancer progression associated with tumor dedifferentiation and poor prognosis.Int J Cancer. 2012 Jan 15;130(2):278-87. doi: 10.1002/ijc.25891. Epub 2011 Nov 9.
• [2] ADAM15 decreases integrin alphavbeta3/vitronectin-mediated ovarian cancer cell adhesion and motility in an RGD-dependent fashion.Int J Biochem Cell Biol. 2005 Mar;37(3):590-603. doi: 10.1016/j.biocel.2004.08.005.
• [3] A disintegrin and metalloproteinase 15 contributes to atherosclerosis by mediating endothelial barrier dysfunction via Src family kinase activity.Arterioscler Thromb Vasc Biol. 2012 Oct;32(10):2444-51. doi: 10.1161/ATVBAHA.112.252205. Epub 2012 Aug 16.
• [4] Altered expression of ADAMs (A Disintegrin And Metalloproteinase) in fibrillating human atria.Circulation. 2002 Feb 12;105(6):720-5. doi: 10.1161/hc0602.103639.
• [5] ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer.PLoS One. 2016 Mar 1;11(3):e0150138. doi: 10.1371/journal.pone.0150138. eCollection 2016.
• [6] ADAM15 mediates upregulation of Claudin-1 expression in breast cancer cells.Sci Rep. 2019 Aug 29;9(1):12540. doi: 10.1038/s41598-019-49021-3.
• [7] Distinct functions of natural ADAM-15 cytoplasmic domain variants in human mammary carcinoma.Mol Cancer Res. 2008 Mar;6(3):383-94. doi: 10.1158/1541-7786.MCR-07-2028. Epub 2008 Feb 22.
• [8] Up-regulation of MDC15 (metargidin) messenger RNA in human osteoarthritic cartilage.Arthritis Rheum. 1999 Sep;42(9):1946-50. doi: 10.1002/1529-0131(199909)42:9<1946::AID-ANR21>3.0.CO;2-E.
• [9] ADAM15 supports prostate cancer metastasis by modulating tumor cell-endothelial cell interaction.Cancer Res. 2008 Feb 15;68(4):1092-9. doi: 10.1158/0008-5472.CAN-07-2432.
• [10] Long non-coding RNA 1308 promotes cell invasion by regulating the miR-124/ADAM 15 axis in non-small-cell lung cancer cells.Cancer Manag Res. 2018 Dec 3;10:6599-6609. doi: 10.2147/CMAR.S187973. eCollection 2018.
• [11] Homeostatic effects of the metalloproteinase disintegrin ADAM15 in degenerative cartilage remodeling.Arthritis Rheum. 2005 Apr;52(4):1100-9. doi: 10.1002/art.20974.
• [12] Increased expression of ADAM 9 and ADAM 15 mRNA in pancreatic cancer.Anticancer Res. 2007 Mar-Apr;27(2):793-9.
• [13] ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas/CD95 Death Signals Into the Activation of Prosurvival Pathways by Calmodulin Recruitment.Arthritis Rheumatol. 2019 Jan;71(1):63-72. doi: 10.1002/art.40667. Epub 2018 Nov 20.
• [14] Expression of ADAM15 in lung carcinomas.Virchows Arch. 2005 Apr;446(4):421-9. doi: 10.1007/s00428-004-1193-z. Epub 2005 Mar 9.
• [15] Melanoma cell-derived vascular endothelial growth factor induces endothelial tubulogenesis within fibrin gels by a metalloproteinase-mediated mechanism.Eur J Cell Biol. 2006 Nov;85(11):1167-77. doi: 10.1016/j.ejcb.2006.07.003. Epub 2006 Sep 1.
• [16] ADAM15 is involved in MICB shedding and mediates the effects of gemcitabine on MICB shedding in PANC-1 pancreatic cancer cells.Mol Med Rep. 2013 Mar;7(3):991-7. doi: 10.3892/mmr.2013.1272. Epub 2013 Jan 11.
• [17] Overexpression of the A Disintegrin and Metalloproteinase ADAM15 is linked to a Small but Highly Aggressive Subset of Prostate Cancers.Neoplasia. 2017 Apr;19(4):279-287. doi: 10.1016/j.neo.2017.01.005. Epub 2017 Mar 8.
• [18] ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease.Neoplasia. 2006 Apr;8(4):319-29. doi: 10.1593/neo.05682.
• [19] Biological properties of melanoma and endothelial cells after plasmid AMEP gene electrotransfer depend on integrin quantity on cells.J Membr Biol. 2013 Nov;246(11):803-19. doi: 10.1007/s00232-013-9550-y. Epub 2013 May 7.
• [20] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [21] 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.
• [22] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [23] 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.
• [24] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [25] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [26] 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.
• [27] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [28] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [29] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [30] 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.