Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTONPC9R)

• DOT Name: LIM domain and actin-binding protein 1 (LIMA1)
• Synonyms: Epithelial protein lost in neoplasm
• Gene Name: LIMA1
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiovascular disease
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
  Esophageal cancer
  Metastatic malignant neoplasm
  Neoplasm
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: LIMA1_HUMAN
• PDB ID: 2D8Y
• Pfam ID: PF00412
• Sequence:
  MESSPFNRRQWTSLSLRVTAKELSLVNKNKSSAIVEIFSKYQKAAEETNMEKKRSNTENL
  SQHFRKGTLTVLKKKWENPGLGAESHTDSLRNSSTEIRHRADHPPAEVTSHAASGAKADQ
  EEQIHPRSRLRSPPEALVQGRYPHIKDGEDLKDHSTESKKMENCLGESRHEVEKSEISEN
  TDASGKIEKYNVPLNRLKMMFEKGEPTQTKILRAQSRSASGRKISENSYSLDDLEIGPGQ
  LSSSTFDSEKNESRRNLELPRLSETSIKDRMAKYQAAVSKQSSSTNYTNELKASGGEIKI
  HKMEQKENVPPGPEVCITHQEGEKISANENSLAVRSTPAEDDSRDSQVKSEVQQPVHPKP
  LSPDSRASSLSESSPPKAMKKFQAPARETCVECQKTVYPMERLLANQQVFHISCFRCSYC
  NNKLSLGTYASLHGRIYCKPHFNQLFKSKGNYDEGFGHRPHKDLWASKNENEEILERPAQ
  LANARETPHSPGVEDAPIAKVGVLAASMEAKASSQQEKEDKPAETKKLRIAWPPPTELGS
  SGSALEEGIKMSKPKWPPEDEISKPEVPEDVDLDLKKLRRSSSLKERSRPFTVAASFQST
  SVKSPKTVSPPIRKGWSMSEQSEESVGGRVAERKQVENAKASKKNGNVGKTTWQNKESKG
  ETGKRSKEGHSLEMENENLVENGADSDEDDNSFLKQQSPQEPKSLNWSSFVDNTFAEEFT
  TQNQKSQDVELWEGEVVKELSVEEQIKRNRYYDEDEDEE
• Function: Actin-binding protein involved in actin cytoskeleton regulation and dynamics. Increases the number and size of actin stress fibers and inhibits membrane ruffling. Inhibits actin filament depolymerization. Bundles actin filaments, delays filament nucleation and reduces formation of branched filaments. Plays a role in cholesterol homeostasis. Influences plasma cholesterol levels through regulation of intestinal cholesterol absorption. May act as a scaffold protein by regulating NPC1L1 transportation, an essential protein for cholesterol absorption, to the plasma membrane by recruiting MYO5B to NPC1L1, and thus facilitates cholesterol uptake.
• Tissue Specificity: Highly expressed in placenta, kidney, pancreas, prostate, ovary, spleen and heart. Also detected in lung, liver, brain, skeletal muscle, thymus, testis and intestine. Not detected in leukocytes. Isoform Beta expressed generally at very low levels. Isoform Alpha abundant in epithelial cells from mammary gland, prostate and in normal oral keratinocytes. Low levels in aortic endothelial cells and dermal fibroblasts. Not detectable in myocardium.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Genetic Variation	[5]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[5]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]

27 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 LIM domain and actin-binding protein 1 (LIMA1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of LIM domain and actin-binding protein 1 (LIMA1).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of LIM domain and actin-binding protein 1 (LIMA1).	[21]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[22]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[23]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[26]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[29]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[33]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[34]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[35]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[36]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of LIM domain and actin-binding protein 1 (LIMA1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of LIM domain and actin-binding protein 1 (LIMA1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of LIM domain and actin-binding protein 1 (LIMA1).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of LIM domain and actin-binding protein 1 (LIMA1).	[28]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of LIM domain and actin-binding protein 1 (LIMA1).	[38]

References

• [1] Mechanistic insights of epithelial protein lost in neoplasm in prostate cancer metastasis.Int J Cancer. 2018 Nov 15;143(10):2537-2550. doi: 10.1002/ijc.31786. Epub 2018 Sep 19.
• [2] MicroRNA profiling with correlation to gene expression revealed the oncogenic miR-17-92 cluster to be up-regulated in osteosarcoma.Cancer Genet. 2012 May;205(5):212-9. doi: 10.1016/j.cancergen.2012.03.001.
• [3] Eplin-alpha expression in human breast cancer, the impact on cellular migration and clinical outcome.Mol Cancer. 2008 Sep 16;7:71. doi: 10.1186/1476-4598-7-71.
• [4] 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.
• [5] Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis.Hum Mol Genet. 2014 Sep 1;23(17):4729-37. doi: 10.1093/hmg/ddu177. Epub 2014 Apr 15.
• [6] Epithelial protein lost in neoplasm- (EPLIN-) is a potential prognostic marker for the progression of epithelial ovarian cancer.Int J Oncol. 2016 Jun;48(6):2488-96. doi: 10.3892/ijo.2016.3462. Epub 2016 Mar 29.
• [7] EPLIN- expression in human oesophageal cancer and its impact on cellular aggressiveness and clinical outcome.Anticancer Res. 2012 Apr;32(4):1283-9.
• [8] Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition.J Biol Chem. 2013 Jan 18;288(3):1469-79. doi: 10.1074/jbc.M112.438341. Epub 2012 Nov 27.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Agonist and antagonist of retinoic acid receptors cause similar changes in gene expression and induce senescence-like growth arrest in MCF-7 breast carcinoma cells. Cancer Res. 2006 Sep 1;66(17):8749-61.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] 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.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [25] 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.
• [26] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [27] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [28] 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.
• [29] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [30] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [31] 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.
• [32] 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.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [34] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [35] 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.
• [36] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [37] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [38] 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.