Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXOM4D9)

• DOT Name: Platelet endothelial cell adhesion molecule (PECAM1)
• Synonyms: PECAM-1; EndoCAM; GPIIA'; PECA1; CD antigen CD31
• Gene Name: PECAM1
• UniProt ID: PECA1_HUMAN
• PDB ID: 2KY5; 5C14; 5GNI
• Pfam ID: PF13895 ; PF13927 ; PF17736
• Sequence:
  MQPRWAQGATMWLGVLLTLLLCSSLEGQENSFTINSVDMKSLPDWTVQNGKNLTLQCFAD
  VSTTSHVKPQHQMLFYKDDVLFYNISSMKSTESYFIPEVRIYDSGTYKCTVIVNNKEKTT
  AEYQVLVEGVPSPRVTLDKKEAIQGGIVRVNCSVPEEKAPIHFTIEKLELNEKMVKLKRE
  KNSRDQNFVILEFPVEEQDRVLSFRCQARIISGIHMQTSESTKSELVTVTESFSTPKFHI
  SPTGMIMEGAQLHIKCTIQVTHLAQEFPEIIIQKDKAIVAHNRHGNKAVYSVMAMVEHSG
  NYTCKVESSRISKVSSIVVNITELFSKPELESSFTHLDQGERLNLSCSIPGAPPANFTIQ
  KEDTIVSQTQDFTKIASKSDSGTYICTAGIDKVVKKSNTVQIVVCEMLSQPRISYDAQFE
  VIKGQTIEVRCESISGTLPISYQLLKTSKVLENSTKNSNDPAVFKDNPTEDVEYQCVADN
  CHSHAKMLSEVLRVKVIAPVDEVQISILSSKVVESGEDIVLQCAVNEGSGPITYKFYREK
  EGKPFYQMTSNATQAFWTKQKASKEQEGEYYCTAFNRANHASSVPRSKILTVRVILAPWK
  KGLIAVVIIGVIIALLIIAAKCYFLRKAKAKQMPVEMSRPAVPLLNSNNEKMSDPNMEAN
  SHYGHNDDVRNHAMKPINDNKEPLNSDVQYTEVQVSSAESHKDLGKKDTETVYSEVRKAV
  PDAVESRYSRTEGSLDGT
• Function: Cell adhesion molecule which is required for leukocyte transendothelial migration (TEM) under most inflammatory conditions. Tyr-690 plays a critical role in TEM and is required for efficient trafficking of PECAM1 to and from the lateral border recycling compartment (LBRC) and is also essential for the LBRC membrane to be targeted around migrating leukocytes. Trans-homophilic interaction may play a role in endothelial cell-cell adhesion via cell junctions. Heterophilic interaction with CD177 plays a role in transendothelial migration of neutrophils. Homophilic ligation of PECAM1 prevents macrophage-mediated phagocytosis of neighboring viable leukocytes by transmitting a detachment signal. Promotes macrophage-mediated phagocytosis of apoptotic leukocytes by tethering them to the phagocytic cells; PECAM1-mediated detachment signal appears to be disabled in apoptotic leukocytes. Modulates bradykinin receptor BDKRB2 activation. Regulates bradykinin- and hyperosmotic shock-induced ERK1/2 activation in endothelial cells. Induces susceptibility to atherosclerosis; [Isoform Delta15]: Does not protect against apoptosis.
• Tissue Specificity: Expressed on platelets and leukocytes and is primarily concentrated at the borders between endothelial cells . Expressed in human umbilical vein endothelial cells (HUVECs) (at protein level) . Expressed on neutrophils (at protein level) . Isoform Long predominates in all tissues examined . Isoform Delta12 is detected only in trachea . Isoform Delta14-15 is only detected in lung . Isoform Delta14 is detected in all tissues examined with the strongest expression in heart . Isoform Delta15 is expressed in brain, testis, ovary, cell surface of platelets, human umbilical vein endothelial cells (HUVECs), Jurkat T-cell leukemia, human erythroleukemia (HEL) and U-937 histiocytic lymphoma cell lines (at protein level) .
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Cell adhesion molecules (hsa04514)
  Leukocyte transendothelial migration (hsa04670)
  Malaria (hsa05144)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  PECAM1 interactions (R-HSA-210990)
  Integrin cell surface interactions (R-HSA-216083)
  Platelet sensitization by LDL (R-HSA-432142)
  Neutrophil degranulation (R-HSA-6798695)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[6]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[7]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[9]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[11]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[12]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[13]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[14]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[15]
Asasantin	DMCZIHT	Approved	Asasantin decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[17]
Curcumin	DMQPH29	Phase 3	Curcumin affects the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[18]
HMPL-004	DM29XGY	Phase 3	HMPL-004 decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[19]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[23]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[24]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[27]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[28]
ISORHAMNETIN	DMQ4Z6E	Investigative	ISORHAMNETIN decreases the expression of Platelet endothelial cell adhesion molecule (PECAM1).	[29]

2 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 Platelet endothelial cell adhesion molecule (PECAM1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Platelet endothelial cell adhesion molecule (PECAM1).	[22]

References

• [1] 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.
• [2] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [3] 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.
• [4] 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.
• [5] Low dosage of arsenic trioxide (As(2)O(3)) inhibits angiogenesis in epithelial ovarian cancer without cell apoptosis. J Biol Inorg Chem. 2018 Aug;23(6):939-947. doi: 10.1007/s00775-018-1595-z. Epub 2018 Jul 16.
• [6] RhoA/MLC signaling pathway is involved in ?-tetrahydrocannabinol-impaired placental angiogenesis. Toxicol Lett. 2018 Mar 15;285:148-155. doi: 10.1016/j.toxlet.2017.12.031. Epub 2018 Jan 4.
• [7] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [8] Possible roles for folic acid in the regulation of trophoblast invasion and placental development in normal early human pregnancy. Biol Reprod. 2011 Jun;84(6):1148-53. doi: 10.1095/biolreprod.110.088351. Epub 2011 Feb 23.
• [9] Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model. Endocr Relat Cancer. 2010 Feb 18;17(1):169-77. doi: 10.1677/ERC-09-0170. Print 2010 Mar.
• [10] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [11] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [12] Thalidomide suppresses angiogenesis and immune evasion via lncRNA FGD5-AS1/miR-454-3p/ZEB1 axis-mediated VEGFA expression and PD-1/PD-L1 checkpoint in NSCLC. Chem Biol Interact. 2021 Nov 1;349:109652. doi: 10.1016/j.cbi.2021.109652. Epub 2021 Sep 11.
• [13] Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways. World J Gastrointest Oncol. 2022 Feb 15;14(2):450-477. doi: 10.4251/wjgo.v14.i2.450.
• [14] Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. Am J Psychiatry. 2005 Jun;162(6):1165-70. doi: 10.1176/appi.ajp.162.6.1165.
• [15] Effects of niacin on cell adhesion and early atherogenesis: biochemical and functional findings in endothelial cells. Basic Clin Pharmacol Toxicol. 2009 Mar;104(3):206-10. doi: 10.1111/j.1742-7843.2008.00364.x. Epub 2009 Jan 21.
• [16] Magnitude and time course of platelet inhibition with Aggrenox and Aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Eur J Pharmacol. 2004 Sep 24;499(3):315-24. doi: 10.1016/j.ejphar.2004.07.114.
• [17] Resveratrol suppresses growth of human ovarian cancer cells in culture and in a murine xenograft model: eukaryotic elongation factor 1A2 as a potential target. Cancer Res. 2009 Sep 15;69(18):7449-58. doi: 10.1158/0008-5472.CAN-09-1266. Epub 2009 Sep 8.
• [18] Opposing effects of curcuminoids on serum stimulated and unstimulated angiogenic response. J Cell Physiol. 2008 Apr;215(1):251-64. doi: 10.1002/jcp.21307.
• [19] Andrographolide reduced VEGFA expression in hepatoma cancer cells by inactivating HIF-1: The involvement of JNK and MTA1/HDCA. Chem Biol Interact. 2017 Aug 1;273:228-236. doi: 10.1016/j.cbi.2017.06.024. Epub 2017 Jun 23.
• [20] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] 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.
• [23] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [24] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [25] Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3. Br J Pharmacol. 2013 Oct;170(4):807-21. doi: 10.1111/bph.12302.
• [26] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [27] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [28] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [29] Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor activation pathway in gastric cancer. J Biol Chem. 2012 Nov 2;287(45):38028-40. doi: 10.1074/jbc.M112.388702. Epub 2012 Sep 19.