Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYPC4XA)

• DOT Name: LIM and calponin homology domains-containing protein 1 (LIMCH1)
• Gene Name: LIMCH1
• Related Disease:
  Advanced cancer
  Drug dependence
  Lung cancer
  Lung carcinoma
  Malignant mesothelioma
  Neoplasm
  Non-small-cell lung cancer
  Substance abuse
  Substance dependence
• UniProt ID: LIMC1_HUMAN
• Pfam ID: PF00307 ; PF15949 ; PF00412
• Sequence:
  MACPALGLEALQPLQPEPPPEPAFSEAQKWIEQVTGRSFGDKDFRTGLENGILLCELLNA
  IKPGLVKKINRLPTPIAGLDNIILFLRGCKELGLKESQLFDPSDLQDTSNRVTVKSLDYS
  RKLKNVLVTIYWLGKAANSCTSYSGTTLNLKEFEGLLAQMRKDTDDIESPKRSIRDSGYI
  DCWDSERSDSLSPPRHGRDDSFDSLDSFGSRSRQTPSPDVVLRGSSDGRGSDSESDLPHR
  KLPDVKKDDMSARRTSHGEPKSAVPFNQYLPNKSNQTAYVPAPLRKKKAEREEYRKSWST
  ATSPLGGERPFRYGPRTPVSDDAESTSMFDMRCEEEAAVQPHSRARQEQLQLINNQLREE
  DDKWQDDLARWKSRRRSVSQDLIKKEEERKKMEKLLAGEDGTSERRKSIKTYREIVQEKE
  RRERELHEAYKNARSQEEAEGILQQYIERFTISEAVLERLEMPKILERSHSTEPNLSSFL
  NDPNPMKYLRQQSLPPPKFTATVETTIARASVLDTSMSAGSGSPSKTVTPKAVPMLTPKP
  YSQPKNSQDVLKTFKVDGKVSVNGETVHREEEKERECPTVAPAHSLTKSQMFEGVARVHG
  SPLELKQDNGSIEINIKKPNSVPQELAATTEKTEPNSQEDKNDGGKSRKGNIELASSEPQ
  HFTTTVTRCSPTVAFVEFPSSPQLKNDVSEEKDQKKPENEMSGKVELVLSQKVVKPKSPE
  PEATLTFPFLDKMPEANQLHLPNLNSQVDSPSSEKSPVMTPQFKFWAWDPEEERRRQEKW
  QQEQERLLQERYQKEQDKLKEEWEKAQKEVEEEERRYYEEERKIIEDTVVPFTVSSSSAD
  QLSTSSSMTEGSGTMNKIDLGNCQDEKQDRRWKKSFQGDDSDLLLKTRESDRLEEKGSLT
  EGALAHSGNPVSKGVHEDHQLDTEAGAPHCGTNPQLAQDPSQNQQTSNPTHSSEDVKPKT
  LPLDKSINHQIESPSERRKKSPREHFQAGPFSPCSPTPPGQSPNRSISGKKLCSSCGLPL
  GKGAAMIIETLNLYFHIQCFRCGICKGQLGDAVSGTDVRIRNGLLNCNDCYMRSRSAGQP
  TTL
• Function: Actin stress fibers-associated protein that activates non-muscle myosin IIa. Activates the non-muscle myosin IIa complex by promoting the phosphorylation of its regulatory subunit MRLC/MYL9. Through the activation of non-muscle myosin IIa, positively regulates actin stress fibers assembly and stabilizes focal adhesions. It therefore negatively regulates cell spreading and cell migration.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Drug dependence	DIS9IXRC	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Substance abuse	DIS327VW	Strong	Biomarker	[2]
Substance dependence	DISDRAAR	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	LIM and calponin homology domains-containing protein 1 (LIMCH1) affects the response to substance of Etoposide.	[29]
Mitomycin	DMH0ZJE	Approved	LIM and calponin homology domains-containing protein 1 (LIMCH1) affects the response to substance of Mitomycin.	[29]

20 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 LIM and calponin homology domains-containing protein 1 (LIMCH1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[19]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[20]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[27]

5 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 LIM and calponin homology domains-containing protein 1 (LIMCH1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[26]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of LIM and calponin homology domains-containing protein 1 (LIMCH1).	[28]

References

• [1] LIMCH1 suppress the growth of lung cancer by interacting with HUWE1 to sustain p53 stability.Gene. 2019 Sep 5;712:143963. doi: 10.1016/j.gene.2019.143963. Epub 2019 Jul 5.
• [2] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [3] MicroRNA and mRNA features of malignant pleural mesothelioma and benign asbestos-related pleural effusion.Biomed Res Int. 2015;2015:635748. doi: 10.1155/2015/635748. Epub 2015 Feb 1.
• [4] LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease.Lung Cancer. 2018 Nov;125:174-184. doi: 10.1016/j.lungcan.2018.09.017. Epub 2018 Sep 24.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] 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.
• [13] 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.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] 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.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] 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.
• [20] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [21] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [22] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [23] 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.
• [24] 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.
• [25] 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.
• [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] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [28] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [29] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.