Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT729S0T)

• DOT Name: LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1)
• Synonyms: Particularly interesting new Cys-His protein 1; PINCH-1; Renal carcinoma antigen NY-REN-48
• Gene Name: LIMS1
• Related Disease:
  Matthew-Wood syndrome
  Nephropathy
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Advanced cancer
  Alzheimer disease
  Colon cancer
  Colon carcinoma
  Gastric adenocarcinoma
  Laryngeal carcinoma
  leukaemia
  Leukemia
  Mucinous adenocarcinoma
  Osteoarthritis
  Squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Glioma
  Acute myelogenous leukaemia
  Clear cell adenocarcinoma
  Neoplasm
• UniProt ID: LIMS1_HUMAN
• PDB ID: 1G47; 1NYP; 1U5S; 2COR; 2D8X; 2KBX; 3F6Q; 4HI8; 4HI9; 6MIF; 7D2S; 7D2T; 7D2U; 7LT9
• Pfam ID: PF00412
• Sequence:
  MANALASATCERCKGGFAPAEKIVNSNGELYHEQCFVCAQCFQQFPEGLFYEFEGRKYCE
  HDFQMLFAPCCHQCGEFIIGRVIKAMNNSWHPECFRCDLCQEVLADIGFVKNAGRHLCRP
  CHNREKARGLGKYICQKCHAIIDEQPLIFKNDPYHPDHFNCANCGKELTADARELKGELY
  CLPCHDKMGVPICGACRRPIEGRVVNAMGKQWHVEHFVCAKCEKPFLGHRHYERKGLAYC
  ETHYNQLFGDVCFHCNRVIEGDVVSALNKAWCVNCFACSTCNTKLTLKNKFVEFDMKPVC
  KKCYEKFPLELKKRLKKLAETLGRK
• Function: Adapter protein in a cytoplasmic complex linking beta-integrins to the actin cytoskeleton, bridges the complex to cell surface receptor tyrosine kinases and growth factor receptors. Involved in the regulation of cell survival, cell proliferation and cell differentiation.
• Tissue Specificity: Expressed in most tissues except in the brain.
• Reactome Pathway:
  Regulation of cytoskeletal remodeling and cell spreading by IPP complex components (R-HSA-446388)
  Cell-extracellular matrix interactions (R-HSA-446353)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[1]
Nephropathy	DISXWP4P	Definitive	Biomarker	[2]
Pancreatic cancer	DISJC981	Definitive	Biomarker	[1]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[6]
Laryngeal carcinoma	DISNHCIV	Strong	Altered Expression	[7]
leukaemia	DISS7D1V	Strong	Biomarker	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[8]
Mucinous adenocarcinoma	DISKNFE8	Strong	Altered Expression	[9]
Osteoarthritis	DIS05URM	Strong	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	moderate	Biomarker	[3]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[3]
Glioma	DIS5RPEH	Disputed	Altered Expression	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[12]
Clear cell adenocarcinoma	DISYUGHZ	Limited	Altered Expression	[13]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[28]

14 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 LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[22]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[23]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[24]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[25]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1).	[27]

References

• [1] LIMS1 Promotes Pancreatic Cancer Cell Survival under Oxygen-Glucose Deprivation Conditions by Enhancing HIF1A Protein Translation.Clin Cancer Res. 2019 Jul 1;25(13):4091-4103. doi: 10.1158/1078-0432.CCR-18-3533. Epub 2019 Jan 24.
• [2] PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase.J Am Soc Nephrol. 2007 Sep;18(9):2534-43. doi: 10.1681/ASN.2007030315. Epub 2007 Jul 26.
• [3] PINCH-1 interacts with myoferlin to promote breast cancer progression and metastasis.Oncogene. 2020 Mar;39(10):2069-2087. doi: 10.1038/s41388-019-1135-5. Epub 2019 Dec 4.
• [4] Autoantibodies to band 3 during aging and disease and aging interventions.Ann N Y Acad Sci. 1994 May 31;719:419-47. doi: 10.1111/j.1749-6632.1994.tb56847.x.
• [5] PINCH-2 presents functional copy number variation and suppresses migration of colon cancer cells by paracrine activity.Int J Cancer. 2015 May 15;136(10):2273-83. doi: 10.1002/ijc.29273. Epub 2014 Oct 30.
• [6] PINCH expression and its clinicopathological significance in gastric adenocarcinoma.Dis Markers. 2012;33(4):171-8. doi: 10.3233/DMA-2012-0930.
• [7] High PINCH1 Expression in Human Laryngeal Carcinoma Associates with Poor Prognosis.Anal Cell Pathol (Amst). 2018 Mar 20;2018:2989635. doi: 10.1155/2018/2989635. eCollection 2018.
• [8] Pinch-1 was up-regulated in leukemia BMSC and its possible effect.Clin Exp Med. 2013 Feb;13(1):21-7. doi: 10.1007/s10238-012-0176-7. Epub 2012 Feb 5.
• [9] Prognostic Significance and Molecular Features of Colorectal Mucinous Adenocarcinomas: A Strobe-Compliant Study.Medicine (Baltimore). 2015 Dec;94(51):e2350. doi: 10.1097/MD.0000000000002350.
• [10] Migfilin's elimination from osteoarthritic chondrocytes further promotes the osteoarthritic phenotype via -catenin upregulation.Biochem Biophys Res Commun. 2013 Jan 11;430(2):494-9. doi: 10.1016/j.bbrc.2012.12.008. Epub 2012 Dec 10.
• [11] Expression of PINCH protein in gliomas and its clinicopathological significance.Oncology. 2007;72(5-6):343-6. doi: 10.1159/000113064. Epub 2008 Jan 12.
• [12] Simultaneous expression of different immunogenic antigens in acute myeloid leukemia.Exp Hematol. 2000 Dec;28(12):1413-22. doi: 10.1016/s0301-472x(00)00550-6.
• [13] Galectin 9 and PINCH, novel immunotherapy targets of renal cell carcinoma: a rationale to find potential tumour antigens and the resulting cytotoxic T lymphocytes induced by the derived peptides.BJU Int. 2014 Feb;113(2):320-32. doi: 10.1111/bju.12499.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] 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.
• [21] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [22] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [23] 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.
• [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] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [26] 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.
• [27] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [28] 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.