Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHT51D6)

• DOT Name: Phospholipid phosphatase 5 (PLPP5)
• Synonyms: EC 3.1.3.4; EC 3.6.1.75; Phosphatidic acid phosphatase type 2 domain-containing protein 1B
• Gene Name: PLPP5
• Related Disease:
  Hepatocellular carcinoma
  Neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Major depressive disorder
  Metastatic malignant neoplasm
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Pancreatic adenocarcinoma
  Small-cell lung cancer
• UniProt ID: PLPP5_HUMAN
• EC Number: 3.1.3.4; 3.6.1.75
• Pfam ID: PF01569
• Sequence:
  MGKAAAAVAFGAEVGVRLALFAAFLVTELLPPFQRLIQPEEMWLYRNPYVEAEYFPTKPM
  FVIAFLSPLSLIFLAKFLKKADTRDSRQACLAASLALALNGVFTNTIKLIVGRPRPDFFY
  RCFPDGLAHSDLMCTGDKDVVNEGRKSFPSGHSSFAFAGLAFASFYLAGKLHCFTPQGRG
  KSWRFCAFLSPLLFAAVIALSRTCDYKHHWQDVLVGSMIGMTFAYVCYRQYYPPLTDAEC
  HKPFQDKLVLSTAQKPGDSYCFDI
• Function: Magnesium-independent phospholipid phosphatase with broad substrate specificity. Preferentially catalyzes the conversion of diacylglycerol pyrophosphate into phosphatidate but can also act on phosphatidate and lysophosphatidate. Phospholipid phosphatases are involved in both the synthesis of lipids and the generation or degradation of lipid-signaling molecules.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
• Reactome Pathway: Role of phospholipids in phagocytosis (R-HSA-2029485)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[1]
Lung cancer	DISCM4YA	Limited	Biomarker	[3]
Lung carcinoma	DISTR26C	Limited	Biomarker	[3]
Lung neoplasm	DISVARNB	Limited	Biomarker	[3]
Pancreatic adenocarcinoma	DISKHX7S	Limited	Biomarker	[3]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[3]

17 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 5 (PLPP5).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phospholipid phosphatase 5 (PLPP5).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phospholipid phosphatase 5 (PLPP5).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phospholipid phosphatase 5 (PLPP5).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Phospholipid phosphatase 5 (PLPP5).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Phospholipid phosphatase 5 (PLPP5).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phospholipid phosphatase 5 (PLPP5).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Phospholipid phosphatase 5 (PLPP5).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Phospholipid phosphatase 5 (PLPP5).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phospholipid phosphatase 5 (PLPP5).	[20]

References

• [1] Genomic aberrations in the HTPAP promoter affect tumor metastasis and clinical prognosis of hepatocellular carcinoma.PLoS One. 2014 Mar 6;9(3):e90528. doi: 10.1371/journal.pone.0090528. eCollection 2014.
• [2] Downregulation of HTPAP transcript variant 1 correlates with tumor metastasis and poor survival in patients with hepatocellular carcinoma.Cancer Sci. 2011 Mar;102(3):583-90. doi: 10.1111/j.1349-7006.2011.01863.x.
• [3] PPAPDC1B and WHSC1L1 are common drivers of the 8p11-12 amplicon, not only in breast tumors but also in pancreatic adenocarcinomas and lung tumors.Am J Pathol. 2013 Nov;183(5):1634-1644. doi: 10.1016/j.ajpath.2013.07.028. Epub 2013 Sep 17.
• [4] Characterization of the recurrent 8p11-12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer.Cancer Res. 2008 Sep 1;68(17):7165-75. doi: 10.1158/0008-5472.CAN-08-1360.
• [5] Identification of commonly altered genes between in major depressive disorder and a mouse model of depression.Sci Rep. 2017 Jun 8;7(1):3044. doi: 10.1038/s41598-017-03291-x.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] 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.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] 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.
• [16] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [20] 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.