Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ7NJGA)

• DOT Name: Phospholipase A-2-activating protein (PLAA)
• Synonyms: PLA2P; PLAP
• Gene Name: PLAA
• Related Disease:
  Adult teratoma
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Choriocarcinoma
  Colon cancer
  Colon carcinoma
  Dysplasia of cervix
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Human papillomavirus infection
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Neoplasm
  Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies
  Ovarian cancer
  Ovarian neoplasm
  Psychotic disorder
  Scleroderma
  Seminoma
  Systemic sclerosis
  Teratoma
  Cutaneous melanoma
  Melanoma
• UniProt ID: PLAP_HUMAN
• PDB ID: 2K89; 2K8A; 2K8B; 2K8C; 3EBB
• Pfam ID: PF09070 ; PF08324 ; PF00400
• Sequence:
  MTSGATRYRLSCSLRGHELDVRGLVCCAYPPGAFVSVSRDRTTRLWAPDSPNRSFTEMHC
  MSGHSNFVSCVCIIPSSDIYPHGLIATGGNDHNICIFSLDSPMPLYILKGHKNTVCSLSS
  GKFGTLLSGSWDTTAKVWLNDKCMMTLQGHTAAVWAVKILPEQGLMLTGSADKTVKLWKA
  GRCERTFSGHEDCVRGLAILSETEFLSCANDASIRRWQITGECLEVYYGHTNYIYSISVF
  PNCRDFVTTAEDRSLRIWKHGECAQTIRLPAQSIWCCCVLDNGDIVVGASDGIIRVFTES
  EDRTASAEEIKAFEKELSHATIDSKTGDLGDINAEQLPGREHLNEPGTREGQTRLIRDGE
  KVEAYQWSVSEGRWIKIGDVVGSSGANQQTSGKVLYEGKEFDYVFSIDVNEGGPSYKLPY
  NTSDDPWLTAYNFLQKNDLNPMFLDQVAKFIIDNTKGQMLGLGNPSFSDPFTGGGRYVPG
  SSGSSNTLPTADPFTGAGRYVPGSASMGTTMAGVDPFTGNSAYRSAASKTMNIYFPKKEA
  VTFDQANPTQILGKLKELNGTAPEEKKLTEDDLILLEKILSLICNSSSEKPTVQQLQILW
  KAINCPEDIVFPALDILRLSIKHPSVNENFCNEKEGAQFSSHLINLLNPKGKPANQLLAL
  RTFCNCFVGQAGQKLMMSQRESLMSHAIELKSGSNKNIHIALATLALNYSVCFHKDHNIE
  GKAQCLSLISTILEVVQDLEATFRLLVALGTLISDDSNAVQLAKSLGVDSQIKKYSSVSE
  PAKVSECCRFILNLL
• Function: Plays a role in protein ubiquitination, sorting and degradation through its association with VCP. Involved in ubiquitin-mediated membrane proteins trafficking to late endosomes in an ESCRT-dependent manner, and hence plays a role in synaptic vesicle recycling. May play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes. Plays a role in cerebellar Purkinje cell development. Positively regulates cytosolic and calcium-independent phospholipase A2 activities in a tumor necrosis factor alpha (TNF-alpha)- or lipopolysaccharide (LPS)-dependent manner, and hence prostaglandin E2 biosynthesis.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult teratoma	DISBY81U	Strong	Altered Expression	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[2]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[3]
Choriocarcinoma	DISDBVNL	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Dysplasia of cervix	DISOAROS	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[7]
Human papillomavirus infection	DISX61LX	Strong	Biomarker	[3]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies	DIS972PH	Strong	Autosomal recessive	[11]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[12]
Scleroderma	DISVQ342	Strong	Genetic Variation	[13]
Seminoma	DIS3J8LJ	Strong	Biomarker	[6]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[13]
Teratoma	DIS6ICY4	Strong	Altered Expression	[1]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[7]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[7]

10 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 Phospholipase A-2-activating protein (PLAA).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phospholipase A-2-activating protein (PLAA).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipase A-2-activating protein (PLAA).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phospholipase A-2-activating protein (PLAA).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phospholipase A-2-activating protein (PLAA).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phospholipase A-2-activating protein (PLAA).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Phospholipase A-2-activating protein (PLAA).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Phospholipase A-2-activating protein (PLAA).	[20]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Phospholipase A-2-activating protein (PLAA).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Phospholipase A-2-activating protein (PLAA).	[22]

References

• [1] Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs.Folia Histochem Cytobiol. 2015;53(3):177-88. doi: 10.5603/FHC.a2015.0020. Epub 2015 Aug 26.
• [2] A novel placental like alkaline phosphatase promoter driven transcriptional silencing combined with single chain variable fragment antibody based virosomal delivery for neoplastic cell targeting [corrected].J Transl Med. 2015 Aug 5;13:254. doi: 10.1186/s12967-015-0602-1.
• [3] HLA DOA1 and DOB1 loci in Honduran women with cervical dysplasia and invasive cervical carcinoma and their relationship to human papillomavirus infection.Hum Biol. 1999 Jun;71(3):367-79.
• [4] Differential expression and butyrate response of human alkaline phosphatase genes are mediated by upstream DNA elements.Biochemistry. 1996 Jul 30;35(30):9807-14. doi: 10.1021/bi9602223.
• [5] Transcriptional regulation of the human placental-like alkaline phosphatase gene and mechanisms involved in its induction by sodium butyrate.Cancer Res. 1992 Jun 15;52(12):3378-83.
• [6] Clinical and biological significance of an isozyme tumor marker--PLAP.Clin Biochem. 1987 Dec;20(6):387-92. doi: 10.1016/0009-9120(87)90003-8.
• [7] Cloning of the human phospholipase A2 activating protein (hPLAP) gene on the chromosome 9p21 melanoma deleted region.Gene. 1999 Oct 18;239(1):155-61. doi: 10.1016/s0378-1119(99)00354-6.
• [8] Phospholipase A2 activating protein and idiopathic inflammatory bowel disease.Gut. 1996 Nov;39(5):698-704. doi: 10.1136/gut.39.5.698.
• [9] Chromosomal localization of phospholipase A2 activating protein, an Ets2 target gene, to 9p21.Genomics. 1999 Dec 15;62(3):529-32. doi: 10.1006/geno.1999.5999.
• [10] Preservation of KIT genotype in a novel pair of patient-derived orthotopic xenograft mouse models of metastatic pediatric CNS germinoma.J Neurooncol. 2016 May;128(1):47-56. doi: 10.1007/s11060-016-2098-9. Epub 2016 Mar 8.
• [11] Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. Brain. 2017 Feb;140(2):370-386. doi: 10.1093/brain/aww295. Epub 2016 Dec 21.
• [12] Common variant at 16p11.2 conferring risk of psychosis.Mol Psychiatry. 2014 Jan;19(1):108-14. doi: 10.1038/mp.2012.157. Epub 2012 Nov 20.
• [13] Unfolding the pathogenesis of scleroderma through genomics and epigenomics.J Autoimmun. 2017 Sep;83:73-94. doi: 10.1016/j.jaut.2017.05.004. Epub 2017 May 16.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [21] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.