Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSSF7BK)

• DOT Name: Phospholipid phosphatase 3 (PLPP3)
• Synonyms: EC 3.1.3.-; EC 3.1.3.4; Lipid phosphate phosphohydrolase 3; PAP2-beta; Phosphatidate phosphohydrolase type 2b; Phosphatidic acid phosphatase 2b; PAP-2b; PAP2b; Vascular endothelial growth factor and type I collagen-inducible protein; VCIP
• Gene Name: PLPP3
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Aortic valve disorder
  Arteriosclerosis
  Atherosclerosis
  Cardiac failure
  Cardiovascular disease
  Colonic neoplasm
  Congestive heart failure
  Coronary atherosclerosis
  Glioblastoma multiforme
  Neoplasm
  Non-alcoholic steatohepatitis
  Myocardial infarction
  Stroke
  Coronary heart disease
• UniProt ID: PLPP3_HUMAN
• EC Number: 3.1.3.-; 3.1.3.4
• Pfam ID: PF01569
• Sequence:
  MQNYKYDKAIVPESKNGGSPALNNNPRRSGSKRVLLICLDLFCLFMAGLPFLIIETSTIK
  PYHRGFYCNDESIKYPLKTGETINDAVLCAVGIVIAILAIITGEFYRIYYLKKSRSTIQN
  PYVAALYKQVGCFLFGCAISQSFTDIAKVSIGRLRPHFLSVCNPDFSQINCSEGYIQNYR
  CRGDDSKVQEARKSFFSGHASFSMYTMLYLVLYLQARFTWRGARLLRPLLQFTLIMMAFY
  TGLSRVSDHKHHPSDVLAGFAQGALVACCIVFFVSDLFKTKTTLSLPAPAIRKEILSPVD
  IIDRNNHHNMM
• Function: Magnesium-independent phospholipid phosphatase of the plasma membrane that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters including phosphatidate/PA, lysophosphatidate/LPA, diacylglycerol pyrophosphate/DGPP, sphingosine 1-phosphate/S1P and ceramide 1-phosphate/C1P. Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound. Has both an extracellular and an intracellular phosphatase activity, allowing the hydrolysis and the cellular uptake of these bioactive lipid mediators from the milieu, regulating signal transduction in different cellular processes. Through the dephosphorylation of extracellular sphingosine-1-phosphate and the regulation of its extra- and intracellular availability, plays a role in vascular homeostasis, regulating endothelial cell migration, adhesion, survival, proliferation and the production of pro-inflammatory cytokines. By maintaining the appropriate levels of this lipid in the cerebellum, also ensure its proper development and function. Through its intracellular lipid phosphatase activity may act in early compartments of the secretory pathway, regulating the formation of Golgi to endoplasmic reticulum retrograde transport carriers ; Independently of this phosphatase activity may also function in the Wnt signaling pathway and the stabilization of beta-catenin/CTNNB1, thereby regulating cell proliferation, migration and differentiation in angiogenesis or yet in tumor growth. Also plays a role in integrin-mediated cell-cell adhesion in angiogenesis.
• Tissue Specificity: Ubiquitously expressed . Highly expressed in heart and placenta .
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Phospholipase D sig.ling pathway (hsa04072)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Fat digestion and absorption (hsa04975)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway: Sphingolipid metabolism (R-HSA-428157)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Aortic valve disorder	DISKLYD7	Strong	Posttranslational Modification	[3]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[4]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[4]
Cardiac failure	DISDC067	Strong	Altered Expression	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[1]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[5]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Non-alcoholic steatohepatitis	DIST4788	Strong	Altered Expression	[8]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[9]
Stroke	DISX6UHX	moderate	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phospholipid phosphatase 3 (PLPP3).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Phospholipid phosphatase 3 (PLPP3).	[21]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[22]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Phospholipid phosphatase 3 (PLPP3).	[23]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[24]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Phospholipid phosphatase 3 (PLPP3).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Phospholipid phosphatase 3 (PLPP3).	[26]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Phospholipid phosphatase 3 (PLPP3).	[27]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Phospholipid phosphatase 3 (PLPP3).	[28]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[22]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Phospholipid phosphatase 3 (PLPP3).	[29]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[22]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Phospholipid phosphatase 3 (PLPP3).	[30]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[22]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Phospholipid phosphatase 3 (PLPP3).	[31]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of Phospholipid phosphatase 3 (PLPP3).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipid phosphatase 3 (PLPP3).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phospholipid phosphatase 3 (PLPP3).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholipid phosphatase 3 (PLPP3).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Phospholipid phosphatase 3 (PLPP3).	[35]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Phospholipid phosphatase 3 (PLPP3).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phospholipid phosphatase 3 (PLPP3).	[26]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Phospholipid phosphatase 3 (PLPP3).	[37]

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 Phospholipid phosphatase 3 (PLPP3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phospholipid phosphatase 3 (PLPP3).	[36]

References

• [1] Lipid phosphate phosphatase-3 regulates tumor growth via -catenin and CYCLIN-D1 signaling.Mol Cancer. 2011 May 11;10:51. doi: 10.1186/1476-4598-10-51.
• [2] Hypoxia Downregulates LPP3 and Promotes the Spatial Segregation of ATX and LPP1 During Cancer Cell Invasion.Cancers (Basel). 2019 Sep 19;11(9):1403. doi: 10.3390/cancers11091403.
• [3] DNA methylation of a PLPP3 MIR transposon-based enhancer promotes an osteogenic programme in calcific aortic valve disease.Cardiovasc Res. 2018 Sep 1;114(11):1525-1535. doi: 10.1093/cvr/cvy111.
• [4] Coronary Artery Disease Risk-Associated Plpp3 Gene and Its Product Lipid Phosphate Phosphatase 3 Regulate Experimental Atherosclerosis.Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2261-2272. doi: 10.1161/ATVBAHA.119.313056. Epub 2019 Sep 19.
• [5] Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.Redox Biol. 2018 Apr;14:261-271. doi: 10.1016/j.redox.2017.09.015. Epub 2017 Sep 28.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] Altered expression of sphingosine-1-phosphate metabolizing enzymes in oral cancer correlate with clinicopathological attributes. Cancer Invest. 2017 Feb 7;35(2):139-141.
• [8] Genomics of human fatty liver disease reveal mechanistically linked lipid droplet-associated gene regulations in bland steatosis and nonalcoholic steatohepatitis.Transl Res. 2016 Nov;177:41-69. doi: 10.1016/j.trsl.2016.06.003. Epub 2016 Jun 16.
• [9] A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.Nat Genet. 2015 Oct;47(10):1121-1130. doi: 10.1038/ng.3396. Epub 2015 Sep 7.
• [10] Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.Stroke. 2014 Jan;45(1):24-36. doi: 10.1161/STROKEAHA.113.002707. Epub 2013 Nov 21.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] 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.
• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [19] 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.
• [20] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [21] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [22] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [23] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [24] 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.
• [25] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [28] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [29] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [30] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [31] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [32] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [33] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [34] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [35] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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.
• [37] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.