Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJL2C79)

• DOT Name: Inactive phospholipase C-like protein 1 (PLCL1)
• Synonyms: PLC-L1; Phospholipase C-deleted in lung carcinoma; Phospholipase C-related but catalytically inactive protein; PRIP
• Gene Name: PLCL1
• Related Disease:
  Bladder transitional cell carcinoma
  Adult respiratory distress syndrome
  Alzheimer disease
  Benign prostatic hyperplasia
  Carcinoma of esophagus
  Castration-resistant prostate carcinoma
  Chronic renal failure
  Clear cell renal carcinoma
  Colorectal carcinoma
  Dermatomyositis
  End-stage renal disease
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Esophagitis
  Gerstmann-Straussler-Scheinker syndrome
  Glioma
  Idiopathic inflammatory myopathy
  Neoplasm
  Neoplasm of esophagus
  Nephrotic syndrome
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Rheumatoid arthritis
  Schizophrenia
  Urinary bladder neoplasm
  Allergic rhinitis
  Bone osteosarcoma
  Coronary heart disease
  Osteosarcoma
  Ulcerative colitis
  Advanced cancer
  Bladder cancer
  Crohn disease
  Cutaneous mastocytosis
  Systemic lupus erythematosus
  Urinary bladder cancer
• UniProt ID: PLCL1_HUMAN
• Pfam ID: PF00168 ; PF09279 ; PF16457 ; PF00388 ; PF00387
• Sequence:
  MAEGAAGREDPAPPDAAGGEDDPRVGPDAAGDCVTAASGGRMRDRRSGVALPGAAGTPAD
  SEAGLLEAARATPRRSSIIKDPSNQKCGGRKKTVSFSSMPSEKKISSANDCISFMQAGCE
  LKKVRPNSRIYNRFFTLDTDLQALRWEPSKKDLEKAKLDISAIKEIRLGKNTETFRNNGL
  ADQICEDCAFSILHGENYESLDLVANSADVANIWVSGLRYLVSRSKQPLDFMEGNQNTPR
  FMWLKTVFEAADVDGNGIMLEDTSVELIKQLNPTLKEAKIRLKFKEIQKSKEKLTTRVTE
  EEFCEAFCELCTRPEVYFLLVQISKNKEYLDANDLMLFLEAEQGVTHITEDICLDIIRRY
  ELSEEGRQKGFLAIDGFTQYLLSSECDIFDPEQKKVAQDMTQPLSHYYINASHNTYLIED
  QFRGPADINGYIRALKMGCRSVELDVSDGSDNEPILCNRNNMTTHVSFRSVIEVINKFAF
  VASEYPLILCLGNHCSLPQQKVMAQQMKKVFGNKLYTEAPLPSESYLPSPEKLKRMIIVK
  GKKLPSDPDVLEGEVTDEDEEAEMSRRMSVDYNGEQKQIRLCRELSDLVSICKSVQYRDF
  ELSMKSQNYWEMCSFSETEASRIANEYPEDFVNYNKKFLSRIYPSAMRIDSSNLNPQDFW
  NCGCQIVAMNFQTPGPMMDLHTGWFLQNGGCGYVLRPSIMRDEVSYFSANTKGILPGVSP
  LALHIKIISGQNFPKPKGACAKGDVIDPYVCIEIHGIPADCSEQRTKTVQQNSDNPIFDE
  TFEFQVNLPELAMIRFVVLDDDYIGDEFIGQYTIPFECLQPGYRHVPLRSFVGDIMEHVT
  LFVHIAITNRSGGGKAQKRSLSVRMGKKVREYTMLRNIGLKTIDDIFKIAVHPLREAIDM
  RENMQNAIVSIKELCGLPPIASLKQCLLTLSSRLITSDNTPSVSLVMKDSFPYLEPLGAI
  PDVQKKMLTAYDLMIQESRFLIEMADTVQEKIVQCQKAGMEFHEELHNLGAKEGLKGRKL
  NKATESFAWNITVLKGQGDLLKNAKNEAIENMKQIQLACLSCGLSKAPSSSAEAKSKRSL
  EAIEEKESSEENGKL
• Function: Involved in an inositol phospholipid-based intracellular signaling cascade. Shows no PLC activity to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol. Component in the phospho-dependent endocytosis process of GABA A receptor. Regulates the turnover of receptors and thus contributes to the maintenance of GABA-mediated synaptic inhibition. Its aberrant expression could contribute to the genesis and progression of lung carcinoma. Acts as an inhibitor of PPP1C.
• Tissue Specificity: Expressed in a variety of fetal and adult organs including brain, lung and kidney. Its expression was greatly reduced in small and non-small cell lung carcinoma. Isoform 1 is predominantly expressed in brain.
• KEGG Pathway: GABAergic sy.pse (hsa04727)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Biomarker	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[5]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[4]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Dermatomyositis	DIS50C5O	Strong	Genetic Variation	[9]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[6]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[10]
Esophagitis	DISHVC9B	Strong	Genetic Variation	[11]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	Strong	Genetic Variation	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[5]
Nephrotic syndrome	DISSPSC2	Strong	Genetic Variation	[6]
Pneumonia	DIS8EF3M	Strong	Biomarker	[2]
Pneumonitis	DIS88E0K	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[13]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[14]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[15]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[16]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[17]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[18]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[17]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[19]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Bladder cancer	DISUHNM0	Limited	Biomarker	[12]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[20]
Cutaneous mastocytosis	DISLBZEF	Limited	Biomarker	[21]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[22]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[12]

12 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 Inactive phospholipase C-like protein 1 (PLCL1).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[25]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[27]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[25]
Prednisolone	DMQ8FR2	Approved	Prednisolone increases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[25]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[25]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[30]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Inactive phospholipase C-like protein 1 (PLCL1).	[25]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Inactive phospholipase C-like protein 1 (PLCL1).	[26]

References

• [1] Knockdown of PLC inhibits inflammatory cytokine release via STAT3 phosphorylation in human bladder cancer cells.Tumour Biol. 2015 Dec;36(12):9723-32. doi: 10.1007/s13277-015-3712-8. Epub 2015 Jul 9.
• [2] Phospholipase C plays a crucial role in neutrophilic inflammation accompanying acute lung injury through augmentation of CXC chemokine production from alveolar epithelial cells.Respir Res. 2019 Jan 11;20(1):9. doi: 10.1186/s12931-019-0975-4.
• [3] APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease.Am J Hum Genet. 1991 Sep;49(3):511-7.
• [4] Combination of phospholipase C knockdown with GANT61 sensitizes castrationresistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway.Oncol Rep. 2019 May;41(5):2689-2702. doi: 10.3892/or.2019.7054. Epub 2019 Mar 7.
• [5] PLCE1 Promotes the Invasion and Migration of Esophageal Cancer Cells by Up-Regulating the PKC/NF-B Pathway.Yonsei Med J. 2018 Dec;59(10):1159-1165. doi: 10.3349/ymj.2018.59.10.1159.
• [6] Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006 Dec;38(12):1397-405. doi: 10.1038/ng1918. Epub 2006 Nov 5.
• [7] Nuclear factor-B signaling pathway is involved in phospholipase C-regulated proliferation in human renal cell carcinoma cells.Mol Cell Biochem. 2014 Apr;389(1-2):265-75. doi: 10.1007/s11010-013-1948-4. Epub 2014 Feb 8.
• [8] Association between phospholipase C epsilon gene (PLCE1) polymorphism and colorectal cancer risk in a Chinese population.J Int Med Res. 2014 Apr;42(2):270-81. doi: 10.1177/0300060513492484. Epub 2014 Feb 4.
• [9] Positive association of genetic variations in the phospholipase C-like 1 gene with dermatomyositis in Chinese Han.Immunol Res. 2016 Feb;64(1):204-12. doi: 10.1007/s12026-015-8738-x.
• [10] Replication study of PLCE1 and C20orf54 polymorphism and risk of esophageal cancer in a Chinese population.Mol Biol Rep. 2012 Sep;39(9):9105-11. doi: 10.1007/s11033-012-1782-x. Epub 2012 Jun 29.
• [11] A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis.Mol Carcinog. 2013 Nov;52 Suppl 1(0 1):E80-6. doi: 10.1002/mc.22016. Epub 2013 Feb 6.
• [12] PLC promotes urinary bladder cancer cells proliferation through STAT3/LDHA pathwaymediated glycolysis.Oncol Rep. 2019 May;41(5):2844-2854. doi: 10.3892/or.2019.7056. Epub 2019 Mar 13.
• [13] Studying the effects of haplotype partitioning methods on the RA-associated genomic results from the North American Rheumatoid Arthritis Consortium (NARAC) dataset.J Adv Res. 2019 Jan 18;18:113-126. doi: 10.1016/j.jare.2019.01.006. eCollection 2019 Jul.
• [14] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [15] Knockdown of phospholipase C-epsilon by short-hairpin RNA-mediated gene silencing induces apoptosis in human bladder cancer cell lines.Cancer Biother Radiopharm. 2013 Apr;28(3):233-9. doi: 10.1089/cbr.2012.1216. Epub 2013 Mar 13.
• [16] Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.Nat Genet. 2018 Aug;50(8):1072-1080. doi: 10.1038/s41588-018-0157-1. Epub 2018 Jul 16.
• [17] Silencing of phosphoinositide-specific phospholipase C remodulates the expression of the phosphoinositide signal transduction pathway in human osteosarcoma cell lines.Anticancer Res. 2014 Aug;34(8):4069-75.
• [18] A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs.Atherosclerosis. 2016 Feb;245:62-70. doi: 10.1016/j.atherosclerosis.2015.11.019. Epub 2015 Nov 22.
• [19] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [20] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [21] Novel Platform of Cardiomyocyte Culture and Coculture via Fibroblast-Derived Matrix-Coupled Aligned Electrospun Nanofiber.ACS Appl Mater Interfaces. 2017 Jan 11;9(1):224-235. doi: 10.1021/acsami.6b14020. Epub 2016 Dec 20.
• [22] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] 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.
• [25] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [26] 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.
• [27] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [30] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.