Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN0BING)

• DOT Name: Plexin-A1 (PLXNA1)
• Synonyms: Semaphorin receptor NOV
• Gene Name: PLXNA1
• Related Disease:
  Epilepsy
  Adenocarcinoma
  Advanced cancer
  Benign prostatic hyperplasia
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Dubowitz syndrome
  Dworschak-Punetha neurodevelopmental syndrome
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastroenteritis
  Hepatocellular carcinoma
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Intervertebral disc degeneration
  Kallmann syndrome
  Neoplasm
  Nephropathy
  Obesity
  Pancreatic cancer
  Prostate adenocarcinoma
  Prostate neoplasm
  Triple negative breast cancer
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Wilms tumor
  Bone osteosarcoma
  Colorectal carcinoma
  Gastric cancer
  Metastatic malignant neoplasm
  Osteosarcoma
  Stomach cancer
  Hyperglycemia
  Hyperlipidemia
  Malignant pleural mesothelioma
  Mesothelioma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: PLXA1_HUMAN
• PDB ID: 7Y4P; 7Y4Q
• Pfam ID: PF08337 ; PF20170 ; PF01437 ; PF01403 ; PF01833 ; PF18020 ; PF17960
• Sequence:
  MPLPPRSLQVLLLLLLLLLLLPGMWAEAGLPRAGGGSQPPFRTFSASDWGLTHLVVHEQT
  GEVYVGAVNRIYKLSGNLTLLRAHVTGPVEDNEKCYPPPSVQSCPHGLGSTDNVNKLLLL
  DYAANRLLACGSASQGICQFLRLDDLFKLGEPHHRKEHYLSSVQEAGSMAGVLIAGPPGQ
  GQAKLFVGTPIDGKSEYFPTLSSRRLMANEEDADMFGFVYQDEFVSSQLKIPSDTLSKFP
  AFDIYYVYSFRSEQFVYYLTLQLDTQLTSPDAAGEHFFTSKIVRLCVDDPKFYSYVEFPI
  GCEQAGVEYRLVQDAYLSRPGRALAHQLGLAEDEDVLFTVFAQGQKNRVKPPKESALCLF
  TLRAIKEKIKERIQSCYRGEGKLSLPWLLNKELGCINSPLQIDDDFCGQDFNQPLGGTVT
  IEGTPLFVDKDDGLTAVAAYDYRGRTVVFAGTRSGRIRKILVDLSNPGGRPALAYESVVA
  QEGSPILRDLVLSPNHQYLYAMTEKQVTRVPVESCVQYTSCELCLGSRDPHCGWCVLHSI
  CSRRDACERADEPQRFAADLLQCVQLTVQPRNVSVTMSQVPLVLQAWNVPDLSAGVNCSF
  EDFTESESVLEDGRIHCRSPSAREVAPITRGQGDQRVVKLYLKSKETGKKFASVDFVFYN
  CSVHQSCLSCVNGSFPCHWCKYRHVCTHNVADCAFLEGRVNVSEDCPQILPSTQIYVPVG
  VVKPITLAARNLPQPQSGQRGYECLFHIPGSPARVTALRFNSSSLQCQNSSYSYEGNDVS
  DLPVNLSVVWNGNFVIDNPQNIQAHLYKCPALRESCGLCLKADPRFECGWCVAERRCSLR
  HHCAADTPASWMHARHGSSRCTDPKILKLSPETGPRQGGTRLTITGENLGLRFEDVRLGV
  RVGKVLCSPVESEYISAEQIVCEIGDASSVRAHDALVEVCVRDCSPHYRALSPKRFTFVT
  PTFYRVSPSRGPLSGGTWIGIEGSHLNAGSDVAVSVGGRPCSFSWRNSREIRCLTPPGQS
  PGSAPIIININRAQLTNPEVKYNYTEDPTILRIDPEWSINSGGTLLTVTGTNLATVREPR
  IRAKYGGIERENGCLVYNDTTMVCRAPSVANPVRSPPELGERPDELGFVMDNVRSLLVLN
  STSFLYYPDPVLEPLSPTGLLELKPSSPLILKGRNLLPPAPGNSRLNYTVLIGSTPCTLT
  VSETQLLCEAPNLTGQHKVTVRAGGFEFSPGTLQVYSDSLLTLPAIVGIGGGGGLLLLVI
  VAVLIAYKRKSRDADRTLKRLQLQMDNLESRVALECKEAFAELQTDIHELTNDLDGAGIP
  FLDYRTYAMRVLFPGIEDHPVLKEMEVQANVEKSLTLFGQLLTKKHFLLTFIRTLEAQRS
  FSMRDRGNVASLIMTALQGEMEYATGVLKQLLSDLIEKNLESKNHPKLLLRRTESVAEKM
  LTNWFTFLLYKFLKECAGEPLFMLYCAIKQQMEKGPIDAITGEARYSLSEDKLIRQQIDY
  KTLTLNCVNPENENAPEVPVKGLDCDTVTQAKEKLLDAAYKGVPYSQRPKAADMDLEWRQ
  GRMARIILQDEDVTTKIDNDWKRLNTLAHYQVTDGSSVALVPKQTSAYNISNSSTFTKSL
  SRYESMLRTASSPDSLRSRTPMITPDLESGTKLWHLVKNHDHLDQREGDRGSKMVSEIYL
  TRLLATKGTLQKFVDDLFETIFSTAHRGSALPLAIKYMFDFLDEQADKHQIHDADVRHTW
  KSNCLPLRFWVNVIKNPQFVFDIHKNSITDACLSVVAQTFMDSCSTSEHKLGKDSPSNKL
  LYAKDIPNYKSWVERYYADIAKMPAISDQDMSAYLAEQSRLHLSQFNSMSALHEIYSYIT
  KYKDEILAALEKDEQARRQRLRSKLEQVVDTMALSS
• Function: Coreceptor for SEMA3A, SEMA3C, SEMA3F and SEMA6D. Necessary for signaling by class 3 semaphorins and subsequent remodeling of the cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration. Class 3 semaphorins bind to a complex composed of a neuropilin and a plexin. The plexin modulates the affinity of the complex for specific semaphorins, and its cytoplasmic domain is required for the activation of down-stream signaling events in the cytoplasm.
• Tissue Specificity: Detected in fetal brain, lung, liver and kidney.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion (R-HSA-399955)
  CRMPs in Sema3A signaling (R-HSA-399956)
  Other semaphorin interactions (R-HSA-416700)
  RHOD GTPase cycle (R-HSA-9013405)
  RND1 GTPase cycle (R-HSA-9696273)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Dubowitz syndrome	DISRMNLQ	Strong	Genetic Variation	[5]
Dworschak-Punetha neurodevelopmental syndrome	DISR5JWN	Strong	Autosomal recessive	[6]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[7]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[9]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Strong	Genetic Variation	[12]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[13]
Kallmann syndrome	DISO3HDG	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Nephropathy	DISXWP4P	Strong	Biomarker	[15]
Obesity	DIS47Y1K	Strong	Biomarker	[16]
Pancreatic cancer	DISJC981	Strong	Biomarker	[17]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[2]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[18]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[19]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[16]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
Wilms tumor	DISB6T16	Strong	Biomarker	[20]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[21]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[22]
Gastric cancer	DISXGOUK	moderate	Biomarker	[23]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[22]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[21]
Stomach cancer	DISKIJSX	moderate	Biomarker	[23]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[24]
Hyperlipidemia	DIS61J3S	Limited	Altered Expression	[24]
Malignant pleural mesothelioma	DIST2R60	Limited	Biomarker	[25]
Mesothelioma	DISKWK9M	Limited	Biomarker	[25]
Prostate cancer	DISF190Y	Limited	Altered Expression	[26]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[26]

3 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 Plexin-A1 (PLXNA1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Plexin-A1 (PLXNA1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Plexin-A1 (PLXNA1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Plexin-A1 (PLXNA1).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Plexin-A1 (PLXNA1).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Plexin-A1 (PLXNA1).	[30]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Plexin-A1 (PLXNA1).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Plexin-A1 (PLXNA1).	[32]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Plexin-A1 (PLXNA1).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Plexin-A1 (PLXNA1).	[35]

References

• [1] Whole exome sequencing reveals novel NOV and DCAF13 variants in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy.Neurosci Lett. 2018 Sep 25;684:115-120. doi: 10.1016/j.neulet.2018.07.014. Epub 2018 Jul 9.
• [2] Differential expression of the ccn3 (nov) proto-oncogene in human prostate cell lines and tissues.Mol Pathol. 2001 Aug;54(4):275-80. doi: 10.1136/mp.54.4.275.
• [3] NOV is upregulated and promotes migration and invasion in bladder cancer.Tumour Biol. 2014 Jul;35(7):6749-55. doi: 10.1007/s13277-014-1919-8. Epub 2014 Apr 10.
• [4] Osteoblasts are "educated" by crosstalk with metastatic breast cancer cells in the bone tumor microenvironment.Breast Cancer Res. 2019 Feb 27;21(1):31. doi: 10.1186/s13058-019-1117-0.
• [5] PLXNA1 developmental encephalopathy with syndromic features: A case report and review of the literature.Am J Med Genet A. 2017 Jul;173(7):1951-1954. doi: 10.1002/ajmg.a.38236. Epub 2017 May 2.
• [6] Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies. Genet Med. 2021 Sep;23(9):1715-1725. doi: 10.1038/s41436-021-01196-9. Epub 2021 May 30.
• [7] Progesterone and 1,25-dihydroxyvitamin D? inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Mol Cancer Res. 2011 Nov;9(11):1479-92. doi: 10.1158/1541-7786.MCR-11-0213. Epub 2011 Sep 20.
• [8] Expression profiles of 290 ESTs mapped to chromosome 3 in human epithelial ovarian cancer cell lines using DNA expression oligonucleotide microarrays.Genome Res. 2002 Jan;12(1):112-21. doi: 10.1101/gr.174202.
• [9] MicroRNA-134 prevents the progression of esophageal squamous cell carcinoma via the PLXNA1-mediated MAPK signalling pathway.EBioMedicine. 2019 Aug;46:66-78. doi: 10.1016/j.ebiom.2019.07.050. Epub 2019 Aug 2.
• [10] Detection and analysis of recombination in GII.4 norovirus strains causing gastroenteritis outbreaks in Alberta.Infect Genet Evol. 2014 Oct;27:181-92. doi: 10.1016/j.meegid.2014.07.016. Epub 2014 Jul 24.
• [11] Expressions of cysteine-rich61, connective tissue growth factor and Nov genes in hepatocellular carcinoma and their clinical significance.World J Gastroenterol. 2004 Dec 1;10(23):3414-8. doi: 10.3748/wjg.v10.i23.3414.
• [12] Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism.Clin Genet. 2019 Feb;95(2):320-324. doi: 10.1111/cge.13482. Epub 2018 Dec 26.
• [13] Bioinformatics analysis of the gene expression profiles in human intervertebral disc degeneration associated with inflammatory cytokines.J Neurosurg Sci. 2018 Feb;62(1):16-23. doi: 10.23736/S0390-5616.16.03326-9. Epub 2015 Jul 22.
• [14] Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?.Cell Commun Signal. 2019 Apr 23;17(1):38. doi: 10.1186/s12964-019-0350-6.
• [15] Reduced NOV/CCN3 Expression Limits Inflammation and Interstitial Renal Fibrosis after Obstructive Nephropathy in Mice.PLoS One. 2015 Sep 14;10(9):e0137876. doi: 10.1371/journal.pone.0137876. eCollection 2015.
• [16] Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development.Int J Mol Sci. 2017 Aug 15;18(8):1770. doi: 10.3390/ijms18081770.
• [17] NOV promoted the growth and migration of pancreatic cancer cells.Tumour Biol. 2014 Apr;35(4):3195-201. doi: 10.1007/s13277-013-1418-3. Epub 2013 Nov 21.
• [18] Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression.Eur Urol. 2018 Mar;73(3):322-339. doi: 10.1016/j.eururo.2017.08.027. Epub 2017 Sep 18.
• [19] Neuropilin-1 Associated Molecules in the Blood Distinguish Poor Prognosis Breast Cancer: A Cross-Sectional Study.Sci Rep. 2017 Jun 12;7(1):3301. doi: 10.1038/s41598-017-03280-0.
• [20] NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia.J Pathol. 2003 Dec;201(4):609-15. doi: 10.1002/path.1468.
• [21] NOV inhibits proliferation while promoting apoptosis and migration in osteosarcoma cell lines through p38/MAPK and JNK/MAPK pathways.Oncol Rep. 2015 Oct;34(4):2011-21. doi: 10.3892/or.2015.4153. Epub 2015 Jul 24.
• [22] Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells.Oncotarget. 2017 Apr 18;8(16):26231-26244. doi: 10.18632/oncotarget.15439.
• [23] Isoprenaline/2-AR activates Plexin-A1/VEGFR2 signals via VEGF secretion in gastric cancer cells to promote tumor angiogenesis.BMC Cancer. 2017 Dec 20;17(1):875. doi: 10.1186/s12885-017-3894-0.
• [24] Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities.Hum Genomics. 2015 Sep 23;9:24. doi: 10.1186/s40246-015-0046-y.
• [25] The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells.Cancer Res. 2009 Feb 15;69(4):1485-93. doi: 10.1158/0008-5472.CAN-08-3659. Epub 2009 Jan 27.
• [26] CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor.Oncogene. 2014 Jan 23;33(4):504-13. doi: 10.1038/onc.2012.602. Epub 2013 Jan 14.
• [27] 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.
• [28] 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.
• [29] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [30] 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.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [32] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [33] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [34] 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.
• [35] 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.
• [36] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.