Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT23OE7H)

• DOT Name: Volume-regulated anion channel subunit LRRC8A (LRRC8A)
• Synonyms: Leucine-rich repeat-containing protein 8A; HsLRRC8A; Swelling protein 1
• Gene Name: LRRC8A
• Related Disease:
  Advanced cancer
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  Hypothyroidism
  Male infertility
  Megalencephalic leukoencephalopathy with subcortical cysts
  Neoplasm
  Stroke
  Autosomal agammaglobulinemia
  Agammaglobulinemia 5, autosomal dominant
  Carcinoma of esophagus
  Colon cancer
  Colon carcinoma
  Esophageal cancer
  Glaucoma/ocular hypertension
  Glioblastoma multiforme
  Metastatic malignant neoplasm
  Obesity
• UniProt ID: LRC8A_HUMAN
• PDB ID: 5ZSU; 6DJB; 7XZH; 8DXN; 8DXO; 8DXP; 8DXQ; 8DXR
• Pfam ID: PF13855 ; PF12534
• Sequence:
  MIPVTELRYFADTQPAYRILKPWWDVFTDYISIVMLMIAVFGGTLQVTQDKMICLPCKWV
  TKDSCNDSFRGWAAPGPEPTYPNSTILPTPDTGPTGIKYDLDRHQYNYVDAVCYENRLHW
  FAKYFPYLVLLHTLIFLACSNFWFKFPRTSSKLEHFVSILLKCFDSPWTTRALSETVVEE
  SDPKPAFSKMNGSMDKKSSTVSEDVEATVPMLQRTKSRIEQGIVDRSETGVLDKKEGEQA
  KALFEKVKKFRTHVEEGDIVYRLYMRQTIIKVIKFILIICYTVYYVHNIKFDVDCTVDIE
  SLTGYRTYRCAHPLATLFKILASFYISLVIFYGLICMYTLWWMLRRSLKKYSFESIREES
  SYSDIPDVKNDFAFMLHLIDQYDPLYSKRFAVFLSEVSENKLRQLNLNNEWTLDKLRQRL
  TKNAQDKLELHLFMLSGIPDTVFDLVELEVLKLELIPDVTIPPSIAQLTGLKELWLYHTA
  AKIEAPALAFLRENLRALHIKFTDIKEIPLWIYSLKTLEELHLTGNLSAENNRYIVIDGL
  RELKRLKVLRLKSNLSKLPQVVTDVGVHLQKLSINNEGTKLIVLNSLKKMANLTELELIR
  CDLERIPHSIFSLHNLQEIDLKDNNLKTIEEIISFQHLHRLTCLKLWYNHIAYIPIQIGN
  LTNLERLYLNRNKIEKIPTQLFYCRKLRYLDLSHNNLTFLPADIGLLQNLQNLAITANRI
  ETLPPELFQCRKLRALHLGNNVLQSLPSRVGELTNLTQIELRGNRLECLPVELGECPLLK
  RSGLVVEEDLFNTLPPEVKERLWRADKEQA
• Function: Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine. Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress. LRRC8A and LRRC8D are required for the uptake of the drug cisplatin. In complex with LRRC8C or LRRC8E, acts as a transporter of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol: mediates both import and export of 2'-3'-cGAMP, thereby promoting transfer of 2'-3'-cGAMP to bystander cells. In contrast, complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP. Required for in vivo channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Can form functional channels by itself (in vitro). Involved in B-cell development: required for the pro-B cell to pre-B cell transition. Also required for T-cell development. Required for myoblast differentiation: VRAC activity promotes membrane hyperpolarization and regulates insulin-stimulated glucose metabolism and oxygen consumption. Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion. Also plays a role in lysosome homeostasis by forming functional lysosomal VRAC channels in response to low cytoplasmic ionic strength condition: lysosomal VRAC channels are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis.
• Tissue Specificity: Expressed in brain, kidney, ovary, lung, liver, heart, and fetal brain and liver. Found at high levels in bone marrow; lower levels are detected in peripheral blood cells. Expressed on T-cells as well as on B-lineage cells.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[5]
Male infertility	DISY3YZZ	Strong	Altered Expression	[6]
Megalencephalic leukoencephalopathy with subcortical cysts	DISK9A1M	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Stroke	DISX6UHX	Strong	Biomarker	[8]
Autosomal agammaglobulinemia	DISRW8BT	Supportive	Autosomal dominant	[9]
Agammaglobulinemia 5, autosomal dominant	DISOVLMN	Limited	Unknown	[9]
Carcinoma of esophagus	DISS6G4D	Limited	Biomarker	[10]
Colon cancer	DISVC52G	Limited	Biomarker	[10]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[10]
Esophageal cancer	DISGB2VN	Limited	Biomarker	[10]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[12]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[10]
Obesity	DIS47Y1K	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[18]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[19]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Volume-regulated anion channel subunit LRRC8A (LRRC8A).	[26]

References

• [1] TTYH1 and TTYH2 Serve as LRRC8A-Independent Volume-Regulated Anion Channels in Cancer Cells.Cells. 2019 Jun 9;8(6):562. doi: 10.3390/cells8060562.
• [2] LRRC8A Expression Influences Growth of Esophageal Squamous Cell Carcinoma.Am J Pathol. 2019 Oct;189(10):1973-1985. doi: 10.1016/j.ajpath.2019.06.006. Epub 2019 Jul 16.
• [3] LRRC8A potentiates temozolomide sensitivity in glioma cells via activating mitochondria-dependent apoptotic pathway.Hum Cell. 2019 Jan;32(1):41-50. doi: 10.1007/s13577-018-0221-2. Epub 2018 Nov 13.
• [4] SWELL1 promotes cell growth and metastasis of hepatocellular carcinoma in vitro and in vivo.EBioMedicine. 2019 Oct;48:100-116. doi: 10.1016/j.ebiom.2019.09.007. Epub 2019 Oct 6.
• [5] 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.
• [6] Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice.JCI Insight. 2018 Aug 23;3(16):e99767. doi: 10.1172/jci.insight.99767. eCollection 2018 Aug 23.
• [7] GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy.Neurobiol Dis. 2018 Nov;119:88-99. doi: 10.1016/j.nbd.2018.07.031. Epub 2018 Aug 1.
• [8] Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke.Neuron. 2019 May 22;102(4):813-827.e6. doi: 10.1016/j.neuron.2019.03.029. Epub 2019 Apr 11.
• [9] A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest. 2003 Dec;112(11):1707-13. doi: 10.1172/JCI18937.
• [10] High expression of leucinerich repeatcontaining8A is indicative of a worse outcome of colon cancer patients by enhancing cancer cell growth and metastasis.Oncol Rep. 2018 Sep;40(3):1275-1286. doi: 10.3892/or.2018.6556. Epub 2018 Jul 10.
• [11] The LRRC8-mediated volume-regulated anion channel is altered in glaucoma.Sci Rep. 2019 Apr 1;9(1):5392. doi: 10.1038/s41598-019-41524-3.
• [12] Downregulation of Leucine-Rich Repeat-Containing 8A Limits Proliferation and Increases Sensitivity of Glioblastoma to Temozolomide and Carmustine.Front Oncol. 2018 May 7;8:142. doi: 10.3389/fonc.2018.00142. eCollection 2018.
• [13] SWELL signalling in adipocytes: can fat 'feel' fat?.Adipocyte. 2019 Dec;8(1):223-228. doi: 10.1080/21623945.2019.1612223.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] 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.
• [19] 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.
• [20] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [21] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] 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.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.