Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT95EBBD)

• DOT Name: Calpain small subunit 1 (CAPNS1)
• Synonyms: CSS1; Calcium-activated neutral proteinase small subunit; CANP small subunit; Calcium-dependent protease small subunit; CDPS; Calcium-dependent protease small subunit 1; Calpain regulatory subunit
• Gene Name: CAPNS1
• Related Disease:
  Advanced cancer
  Breast neoplasm
  Clear cell renal carcinoma
  Duchenne muscular dystrophy
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  Lung cancer
  Lung carcinoma
  Nasopharyngeal carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate carcinoma
  Prostate neoplasm
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Epstein barr virus infection
  Prediabetes syndrome
  Prostate cancer
• UniProt ID: CPNS1_HUMAN
• PDB ID: 1KFU; 1KFX; 4PHJ; 4PHK; 4PHM; 4WQ2; 4WQ3; 5D69; 6QLB
• Sequence:
  MFLVNSFLKGGGGGGGGGGGLGGGLGNVLGGLISGAGGGGGGGGGGGGGGGGGGGGTAMR
  ILGGVISAISEAAAQYNPEPPPPRTHYSNIEANESEEVRQFRRLFAQLAGDDMEVSATEL
  MNILNKVVTRHPDLKTDGFGIDTCRSMVAVMDSDTTGKLGFEEFKYLWNNIKRWQAIYKQ
  FDTDRSGTICSSELPGAFEAAGFHLNEHLYNMIIRRYSDESGNMDFDNFISCLVRLDAMF
  RAFKSLDKDGTGQIQVNIQEWLQLTMYS
• Function: Regulatory subunit of the calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Essential for embryonic development.
• KEGG Pathway: Shigellosis (hsa05131)
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models (R-HSA-8862803)
  Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[11]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[12]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[13]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[13]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[14]
Epstein barr virus infection	DISOO0WT	Limited	Altered Expression	[15]
Prediabetes syndrome	DISH2I53	Limited	Biomarker	[16]
Prostate cancer	DISF190Y	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Calpain small subunit 1 (CAPNS1) increases the response to substance of Cisplatin.	[31]
Sulforaphane	DMQY3L0	Investigative	Calpain small subunit 1 (CAPNS1) affects the binding of Sulforaphane.	[32]

16 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 Calpain small subunit 1 (CAPNS1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calpain small subunit 1 (CAPNS1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calpain small subunit 1 (CAPNS1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Calpain small subunit 1 (CAPNS1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Calpain small subunit 1 (CAPNS1).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Calpain small subunit 1 (CAPNS1).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Calpain small subunit 1 (CAPNS1).	[23]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Calpain small subunit 1 (CAPNS1).	[24]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Calpain small subunit 1 (CAPNS1).	[25]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Calpain small subunit 1 (CAPNS1).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Calpain small subunit 1 (CAPNS1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calpain small subunit 1 (CAPNS1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Calpain small subunit 1 (CAPNS1).	[28]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Calpain small subunit 1 (CAPNS1).	[29]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Calpain small subunit 1 (CAPNS1).	[30]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Calpain small subunit 1 (CAPNS1).	[22]

References

• [1] Capn4 promotes esophageal squamous cell carcinoma metastasis by regulating ZEB1 through the Wnt/-catenin signaling pathway.Thorac Cancer. 2019 Jan;10(1):24-32. doi: 10.1111/1759-7714.12893. Epub 2018 Nov 15.
• [2] The oncoprotein HBXIP enhances migration of breast cancer cells through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling.Cancer Lett. 2014 Dec 28;355(2):288-96. doi: 10.1016/j.canlet.2014.09.047. Epub 2014 Oct 7.
• [3] Capn4 contributes to tumor invasion and metastasis in clear cell renal cell carcinoma cells via modulating talin-focal adhesion kinase signaling pathway.Acta Biochim Biophys Sin (Shanghai). 2018 May 1;50(5):465-472. doi: 10.1093/abbs/gmy031.
• [4] Importance of monitoring calcium & calcium related properties in carrier detection for Duchenne muscular dystrophy.Indian J Med Res. 1994 Jun;99:283-8.
• [5] Capn4 overexpression indicates poor prognosis of ovarian cancer patients.J Cancer. 2018 Jan 1;9(2):304-309. doi: 10.7150/jca.22004. eCollection 2018.
• [6] Increased expression of Capn4 is associated with the malignancy of human glioma.CNS Neurosci Ther. 2014 Jun;20(6):521-7. doi: 10.1111/cns.12248. Epub 2014 Mar 15.
• [7] Prognostic significance of Capn4 overexpression in intrahepatic cholangiocarcinoma.PLoS One. 2013;8(1):e54619. doi: 10.1371/journal.pone.0054619. Epub 2013 Jan 22.
• [8] Capn4 promotes non-small cell lung cancer progression via upregulation of matrix metalloproteinase 2.Med Oncol. 2015 Mar;32(3):51. doi: 10.1007/s12032-015-0500-7. Epub 2015 Jan 31.
• [9] Capn4 is induced by and required for Epstein-Barr virus latent membrane protein 1 promotion of nasopharyngeal carcinoma metastasis through ERK/AP-1 signaling.Cancer Sci. 2020 Jan;111(1):72-83. doi: 10.1111/cas.14227. Epub 2019 Nov 25.
• [10] Obesity-associated dysregulation of calpastatin and MMP-15 in adipose-derived stromal cells results in their enhanced invasion.Stem Cells. 2012 Dec;30(12):2774-83. doi: 10.1002/stem.1229.
• [11] Capn4 expression is modulated by microRNA-520b and exerts an oncogenic role in prostate cancer cells by promoting Wnt/-catenin signaling.Biomed Pharmacother. 2018 Dec;108:467-475. doi: 10.1016/j.biopha.2018.09.019. Epub 2018 Sep 18.
• [12] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [13] Calpain4 is required for activation of HER2 in breast cancer cells exposed to trastuzumab and its suppression decreases survival and enhances response.Int J Cancer. 2012 Nov 15;131(10):2420-32. doi: 10.1002/ijc.27510. Epub 2012 Mar 28.
• [14] Capn4 promotes colorectal cancer cell proliferation by increasing MAPK7 through activation of the Wnt/-Catenin pathway.Exp Cell Res. 2018 Feb 15;363(2):235-242. doi: 10.1016/j.yexcr.2018.01.013. Epub 2018 Jan 10.
• [15] Capn4 is a marker of poor clinical outcomes and promotes nasopharyngeal carcinoma metastasis via nuclear factor-B-induced matrix metalloproteinase 2 expression.Cancer Sci. 2014 Jun;105(6):630-8. doi: 10.1111/cas.12416. Epub 2014 May 21.
• [16] Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis.Diabetologia. 2019 May;62(5):860-872. doi: 10.1007/s00125-019-4828-y. Epub 2019 Feb 18.
• [17] 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.
• [18] 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.
• [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] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [22] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [23] 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.
• [24] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [25] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [26] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [27] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [28] 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.
• [29] 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.
• [30] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [31] MiR-99a and MiR-491 Regulate Cisplatin Resistance in Human Gastric Cancer Cells by Targeting CAPNS1. Int J Biol Sci. 2016 Nov 5;12(12):1437-1447. doi: 10.7150/ijbs.16529. eCollection 2016.
• [32] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.