Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6WFVXZ)

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1)
• Synonyms: EC 3.1.4.11; Phosphoinositide phospholipase C-delta-1; Phospholipase C-III; PLC-III; Phospholipase C-delta-1; PLC-delta-1
• Gene Name: PLCD1
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Coronary vasospasm
  Cystic fibrosis
  Esophageal squamous cell carcinoma
  Gastric cancer
  High blood pressure
  Impulse control disorder
  Irritant contact dermatitis
  Lung cancer
  Lung carcinoma
  Myocardial ischemia
  Nonsyndromic congenital nail disorder 3
  Psoriasis
  Skin disease
  Squamous cell carcinoma
  Stomach cancer
  Trichilemmal cyst
  Triple negative breast cancer
  Alopecia
  Carcinoma
  Matthew-Wood syndrome
  Neoplasm
  Tuberous sclerosis
  Amyotrophic lateral sclerosis
  Hypotension
  Osteoarthritis
• UniProt ID: PLCD1_HUMAN
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF09279 ; PF16457 ; PF00388 ; PF00387
• Sequence:
  MDSGRDFLTLHGLQDDEDLQALLKGSQLLKVKSSSWRRERFYKLQEDCKTIWQESRKVMR
  TPESQLFSIEDIQEVRMGHRTEGLEKFARDVPEDRCFSIVFKDQRNTLDLIAPSPADAQH
  WVLGLHKIIHHSGSMDQRQKLQHWIHSCLRKADKNKDNKMSFKELQNFLKELNIQVDDSY
  ARKIFRECDHSQTDSLEDEEIEAFYKMLTQRVEIDRTFAEAAGSGETLSVDQLVTFLQHQ
  QREEAAGPALALSLIERYEPSETAKAQRQMTKDGFLMYLLSADGSAFSLAHRRVYQDMGQ
  PLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTF
  TSKILFCDVLRAIRDYAFKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLDG
  VTNSLPSPEQLKGKILLKGKKLGGLLPPGGEGGPEATVVSDEDEAAEMEDEAVRSRVQHK
  PKEDKLRLAQELSDMVIYCKSVHFGGFSSPGTPGQAFYEMASFSENRALRLLQESGNGFV
  RHNVGHLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYQGRFQDNGACG
  YVLKPAFLRDPNGTFNPRALAQGPWWARKRLNIRVISGQQLPKVNKNKNSIVDPKVTVEI
  HGVSRDVASRQTAVITNNGFNPWWDTEFAFEVVVPDLALIRFLVEDYDASSKNDFIGQST
  IPLNSLKQGYRHVHLMSKNGDQHPSATLFVKISLQD
• Function: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. Essential for trophoblast and placental development. Binds phosphatidylinositol 4,5-bisphosphate.
• Tissue Specificity: Strongly expressed in lung, liver and heart. Also expressed at least in pancreas, kidney, skeletal muscle, placenta and brain.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Calcium sig.ling pathway (hsa04020)
  Phosphatidylinositol sig.ling system (hsa04070)
  Thyroid hormone sig.ling pathway (hsa04919)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Shigellosis (hsa05131)
• Reactome Pathway: Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
• BioCyc Pathway: MetaCyc:HS07195-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Definitive	Biomarker	[1]
Congestive heart failure	DIS32MEA	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Coronary vasospasm	DISSHV10	Strong	Altered Expression	[5]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
High blood pressure	DISY2OHH	Strong	Biomarker	[9]
Impulse control disorder	DISRIYJ5	Strong	Biomarker	[10]
Irritant contact dermatitis	DIS62JY3	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[11]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[11]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[12]
Nonsyndromic congenital nail disorder 3	DISHS12J	Strong	Autosomal recessive	[13]
Psoriasis	DIS59VMN	Strong	Biomarker	[14]
Skin disease	DISDW8R6	Strong	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[7]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Trichilemmal cyst	DISLWEDU	Strong	Biomarker	[15]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[16]
Alopecia	DIS37HU4	moderate	Biomarker	[17]
Carcinoma	DISH9F1N	moderate	Altered Expression	[18]
Matthew-Wood syndrome	DISA7HR7	moderate	Altered Expression	[19]
Neoplasm	DISZKGEW	moderate	Biomarker	[3]
Tuberous sclerosis	DISEMUGZ	moderate	Altered Expression	[20]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[21]
Hypotension	DISYNSM9	Limited	SusceptibilityMutation	[22]
Osteoarthritis	DIS05URM	Limited	Biomarker	[23]

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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[25]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[27]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[29]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1).	[34]

References

• [1] Depressed responsiveness of phospholipase C isoenzymes to phosphatidic acid in congestive heart failure.J Mol Cell Cardiol. 2001 Mar;33(3):431-40. doi: 10.1006/jmcc.2000.1315.
• [2] Phospholipase C1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells.Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13505-10. doi: 10.1073/pnas.1405374111. Epub 2014 Sep 2.
• [3] Phospholipase C1 suppresses cell migration and invasion of breast cancer cells by modulating KIF3A-mediated ERK1/2/- catenin/MMP7 signalling.Oncotarget. 2017 Apr 25;8(17):29056-29066. doi: 10.18632/oncotarget.16072.
• [4] Methylation of PLCD1 and adenovirus-mediated PLCD1 overexpression elicits a gene therapy effect on human breast cancer.Exp Cell Res. 2015 Mar 15;332(2):179-89. doi: 10.1016/j.yexcr.2015.01.017. Epub 2015 Feb 2.
• [5] Enhanced transient receptor potential channel-mediated Ca(2+) influx in the cells with phospholipase C-1 overexpression: its possible role in coronary artery spasm.Fundam Clin Pharmacol. 2017 Aug;31(4):383-391. doi: 10.1111/fcp.12269. Epub 2017 Feb 16.
• [6] The low PLC-1 expression in cystic fibrosis bronchial epithelial cells induces upregulation of TRPV6 channel activity.Cell Calcium. 2015 Jan;57(1):38-48. doi: 10.1016/j.ceca.2014.11.005. Epub 2014 Nov 18.
• [7] Characterization of a novel tumor-suppressor gene PLC delta 1 at 3p22 in esophageal squamous cell carcinoma.Cancer Res. 2007 Nov 15;67(22):10720-6. doi: 10.1158/0008-5472.CAN-07-2411.
• [8] Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer.Oncogene. 2009 Jul 2;28(26):2466-75. doi: 10.1038/onc.2009.92. Epub 2009 May 18.
• [9] Increased expression and activity of phospholipase C in renal arterioles of young spontaneously hypertensive rats.Am J Hypertens. 2007 Jan;20(1):38-43. doi: 10.1016/j.amjhyper.2006.06.009.
• [10] Epidermal loss of phospholipase C1 attenuates irritant contact dermatitis.Biochem Biophys Res Commun. 2019 Apr 2;511(2):330-335. doi: 10.1016/j.bbrc.2019.02.046. Epub 2019 Feb 18.
• [11] Genomic structure of the human PLCD1 (phospholipase C delta 1) locus on 3p22-->p21.3.Cytogenet Cell Genet. 1997;78(1):58-60. doi: 10.1159/000134629.
• [12] Phospholipase C-delta1 rescues intracellular Ca2+ overload in ischemic heart and hypoxic neonatal cardiomyocytes.J Steroid Biochem Mol Biol. 2004 Jul;91(3):131-8. doi: 10.1016/j.jsbmb.2004.02.009.
• [13] Hereditary leukonychia, or porcelain nails, resulting from mutations in PLCD1. Am J Hum Genet. 2011 Jun 10;88(6):839-844. doi: 10.1016/j.ajhg.2011.05.014.
• [14] Epidermal phospholipase C1 regulates granulocyte counts and systemic interleukin-17 levels in mice.Nat Commun. 2012 Jul 17;3:963. doi: 10.1038/ncomms1960.
• [15] A Monoallelic Two-Hit Mechanism in PLCD1 Explains the Genetic Pathogenesis of Hereditary Trichilemmal Cyst Formation.J Invest Dermatol. 2019 Oct;139(10):2154-2163.e5. doi: 10.1016/j.jid.2019.04.015. Epub 2019 May 11.
• [16] The Gh-PLC1 signaling axis drives metastatic progression in triple-negative breast cancer.J Hematol Oncol. 2017 Jun 2;10(1):114. doi: 10.1186/s13045-017-0481-4.
• [17] Abnormalities of hair structure and skin histology derived from CRISPR/Cas9-based knockout of phospholipase C-delta 1 in mice.J Transl Med. 2018 May 25;16(1):141. doi: 10.1186/s12967-018-1512-9.
• [18] Phospholipase C isozymes are deregulated in colorectal cancer--insights gained from gene set enrichment analysis of the transcriptome.PLoS One. 2011;6(9):e24419. doi: 10.1371/journal.pone.0024419. Epub 2011 Sep 1.
• [19] Noteworthy prognostic value of phospholipase C delta genes in early stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy and potential molecular mechanisms.Cancer Med. 2020 Feb;9(3):859-871. doi: 10.1002/cam4.2699. Epub 2019 Dec 6.
• [20] Elevated Expression of TRPC4 in Cortical Lesions of Focal Cortical Dysplasia II and Tuberous Sclerosis Complex.J Mol Neurosci. 2017 Jun;62(2):222-231. doi: 10.1007/s12031-017-0923-z. Epub 2017 Apr 28.
• [21] Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice.Neurobiol Dis. 2013 Dec;60:11-7. doi: 10.1016/j.nbd.2013.08.006. Epub 2013 Aug 19.
• [22] Hypotensive effect associated with a phospholipase C-delta 1 gene mutation in the spontaneously hypertensive rat.Biochem Biophys Res Commun. 1992 Sep 30;187(3):1359-66. doi: 10.1016/0006-291x(92)90452-q.
• [23] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [24] 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.
• [25] 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.
• [26] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [27] 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.
• [28] 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.
• [29] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [30] 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.
• [31] 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.
• [32] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [33] 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.
• [34] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.