Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1CLR5L)

DOT Name Kunitz-type protease inhibitor 1 (SPINT1)
Synonyms Hepatocyte growth factor activator inhibitor type 1; HAI-1
Gene Name SPINT1
Related Disease
Prostate cancer ( )
Prostate carcinoma ( )
Type-1/2 diabetes ( )
Adenocarcinoma ( )
Autism spectrum disorder ( )
Breast cancer ( )
Breast carcinoma ( )
Breast neoplasm ( )
Carcinoma ( )
Chronic obstructive pulmonary disease ( )
Clear cell renal carcinoma ( )
Colorectal adenocarcinoma ( )
Colorectal neoplasm ( )
Cutaneous melanoma ( )
Differentiated thyroid carcinoma ( )
Endometrial cancer ( )
Endometrial carcinoma ( )
Epithelial ovarian cancer ( )
Esophageal squamous cell carcinoma ( )
Hepatitis ( )
Hepatitis A virus infection ( )
Hepatitis B virus infection ( )
Influenza ( )
Intestinal neoplasm ( )
Liver cirrhosis ( )
Melanoma ( )
Neoplasm ( )
Non-small-cell lung cancer ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Prostate neoplasm ( )
Pulmonary fibrosis ( )
Renal cell carcinoma ( )
Thyroid gland follicular carcinoma ( )
Thyroid gland papillary carcinoma ( )
Gastric cancer ( )
Hepatocellular carcinoma ( )
Stomach cancer ( )
Primary biliary cholangitis ( )
Adult glioblastoma ( )
Benign prostatic hyperplasia ( )
Colorectal carcinoma ( )
Glioblastoma multiforme ( )
Hepatitis C virus infection ( )
Leiomyoma ( )
Squamous cell carcinoma ( )
Tuberous sclerosis ( )
Uterine fibroids ( )
UniProt ID
SPIT1_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1YC0; 2MSX; 4ISL; 4ISN; 4ISO; 5EZD; 5H7V
Pfam ID
PF00014 ; PF00057 ; PF07502
Sequence
MAPARTMARARLAPAGIPAVALWLLCTLGLQGTQAGPPPAPPGLPAGADCLNSFTAGVPG
FVLDTNASVSNGATFLESPTVRRGWDCVRACCTTQNCNLALVELQPDRGEDAIAACFLIN
CLYEQNFVCKFAPREGFINYLTREVYRSYRQLRTQGFGGSGIPKAWAGIDLKVQPQEPLV
LKDVENTDWRLLRGDTDVRVERKDPNQVELWGLKEGTYLFQLTVTSSDHPEDTANVTVTV
LSTKQTEDYCLASNKVGRCRGSFPRWYYDPTEQICKSFVYGGCLGNKNNYLREEECILAC
RGVQGGPLRGSSGAQATFPQGPSMERRHPVCSGTCQPTQFRCSNGCCIDSFLECDDTPNC
PDASDEAACEKYTSGFDELQRIHFPSDKGHCVDLPDTGLCKESIPRWYYNPFSEHCARFT
YGGCYGNKNNFEEEQQCLESCRGISKKDVFGLRREIPIPSTGSVEMAVAVFLVICIVVVV
AILGYCFFKNQRKDFHGHHHHPPPTPASSTVSTTEDTEHLVYNHTTRPL
Function Inhibitor of HGFAC. Inhibits serine protease activity of ST14/matriptase in vitro. Inhibits serine protease activity of TMPRSS13, via the BPTI/Kunitz inhibitor 1 domain.
KEGG Pathway
Transcriptio.l misregulation in cancer (hsa05202 )
Prostate cancer (hsa05215 )
Reactome Pathway
Signaling by MST1 (R-HSA-8852405 )
MET Receptor Activation (R-HSA-6806942 )

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Prostate cancer DISF190Y Definitive Altered Expression [1]
Prostate carcinoma DISMJPLE Definitive Altered Expression [1]
Type-1/2 diabetes DISIUHAP Definitive Biomarker [2]
Adenocarcinoma DIS3IHTY Strong Altered Expression [3]
Autism spectrum disorder DISXK8NV Strong Biomarker [4]
Breast cancer DIS7DPX1 Strong Genetic Variation [5]
Breast carcinoma DIS2UE88 Strong Genetic Variation [5]
Breast neoplasm DISNGJLM Strong Biomarker [6]
Carcinoma DISH9F1N Strong Biomarker [7]
Chronic obstructive pulmonary disease DISQCIRF Strong Genetic Variation [8]
Clear cell renal carcinoma DISBXRFJ Strong Biomarker [9]
Colorectal adenocarcinoma DISPQOUB Strong Altered Expression [3]
Colorectal neoplasm DISR1UCN Strong Altered Expression [10]
Cutaneous melanoma DIS3MMH9 Strong Genetic Variation [11]
Differentiated thyroid carcinoma DIS1V20Y Strong Altered Expression [12]
Endometrial cancer DISW0LMR Strong Biomarker [13]
Endometrial carcinoma DISXR5CY Strong Biomarker [13]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [14]
Esophageal squamous cell carcinoma DIS5N2GV Strong Altered Expression [15]
Hepatitis DISXXX35 Strong Biomarker [16]
Hepatitis A virus infection DISUMFQV Strong Biomarker [16]
Hepatitis B virus infection DISLQ2XY Strong Genetic Variation [17]
Influenza DIS3PNU3 Strong Biomarker [18]
Intestinal neoplasm DISK0GUH Strong Biomarker [19]
Liver cirrhosis DIS4G1GX Strong Biomarker [17]
Melanoma DIS1RRCY Strong Genetic Variation [11]
Neoplasm DISZKGEW Strong Altered Expression [15]
Non-small-cell lung cancer DIS5Y6R9 Strong Altered Expression [20]
Ovarian cancer DISZJHAP Strong Biomarker [14]
Ovarian neoplasm DISEAFTY Strong Biomarker [14]
Prostate neoplasm DISHDKGQ Strong Biomarker [21]
Pulmonary fibrosis DISQKVLA Strong Biomarker [22]
Renal cell carcinoma DISQZ2X8 Strong Biomarker [9]
Thyroid gland follicular carcinoma DISFK2QT Strong Altered Expression [12]
Thyroid gland papillary carcinoma DIS48YMM Strong Altered Expression [12]
Gastric cancer DISXGOUK moderate Biomarker [23]
Hepatocellular carcinoma DIS0J828 moderate Altered Expression [24]
Stomach cancer DISKIJSX moderate Biomarker [23]
Primary biliary cholangitis DIS43E0O Disputed Altered Expression [25]
Adult glioblastoma DISVP4LU Limited Biomarker [26]
Benign prostatic hyperplasia DISI3CW2 Limited Altered Expression [1]
Colorectal carcinoma DIS5PYL0 Limited Biomarker [11]
Glioblastoma multiforme DISK8246 Limited Biomarker [26]
Hepatitis C virus infection DISQ0M8R Limited Genetic Variation [27]
Leiomyoma DISLDDFN Limited Altered Expression [28]
Squamous cell carcinoma DISQVIFL Limited Biomarker [11]
Tuberous sclerosis DISEMUGZ Limited Biomarker [29]
Uterine fibroids DISBZRMJ Limited Altered Expression [28]
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⏷ Show the Full List of 48 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
11 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 Kunitz-type protease inhibitor 1 (SPINT1). [30]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [31]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [32]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [33]
Triclosan DMZUR4N Approved Triclosan increases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [34]
Marinol DM70IK5 Approved Marinol decreases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [35]
Selenium DM25CGV Approved Selenium increases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [36]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [38]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [39]
Sulforaphane DMQY3L0 Investigative Sulforaphane decreases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [40]
Nitrobenzanthrone DMN6L70 Investigative Nitrobenzanthrone decreases the expression of Kunitz-type protease inhibitor 1 (SPINT1). [41]
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⏷ Show the Full List of 11 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Kunitz-type protease inhibitor 1 (SPINT1). [37]
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References

1 Expression of hepatocyte growth factor activator inhibitor-1 (HAI-1) gene in prostate cancer: clinical and biological significance.J BUON. 2014 Jan-Mar;19(1):215-20.
2 Predictors of acute kidney injury (AKI) in high-risk ST-elevation myocardial infarction (STEMI) patients: A single-center retrospective observational study.Bosn J Basic Med Sci. 2019 Feb 12;19(1):101-108. doi: 10.17305/bjbms.2018.3797.
3 Paradoxically enhanced immunoreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in cancer cells at the invasion front.Cancer Sci. 2004 Sep;95(9):728-35. doi: 10.1111/j.1349-7006.2004.tb03253.x.
4 Circumscribed interests in adolescents with Autism Spectrum Disorder: A look beyond trains, planes, and clocks.PLoS One. 2017 Nov 2;12(11):e0187414. doi: 10.1371/journal.pone.0187414. eCollection 2017.
5 ST14 gene variant and decreased matriptase protein expression predict poor breast cancer survival.Cancer Epidemiol Biomarkers Prev. 2010 Sep;19(9):2133-42. doi: 10.1158/1055-9965.EPI-10-0418. Epub 2010 Aug 17.
6 Macrophage HIF-2 regulates tumor-suppressive Spint1 in the tumor microenvironment.Mol Carcinog. 2019 Nov;58(11):2127-2138. doi: 10.1002/mc.23103. Epub 2019 Aug 22.
7 Activation of hepatocyte growth factor/scatter factor in colorectal carcinoma.Cancer Res. 2000 Nov 1;60(21):6148-59.
8 The protease inhibitor PI*S allele and COPD: a meta-analysis.Eur Respir J. 2005 Jul;26(1):67-76. doi: 10.1183/09031936.05.00135704.
9 Hepatocyte growth factor activator inhibitor types 1 and 2 are expressed by tubular epithelium in kidney and down-regulated in renal cell carcinoma.J Urol. 2004 Feb;171(2 Pt 1):890-6. doi: 10.1097/01.ju.0000092861.21122.d2.
10 The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals.BMC Cancer. 2006 Jul 4;6:176. doi: 10.1186/1471-2407-6-176.
11 Zebrafish modeling reveals that SPINT1 regulates the aggressiveness of skin cutaneous melanoma and its crosstalk with tumor immune microenvironment.J Exp Clin Cancer Res. 2019 Sep 13;38(1):405. doi: 10.1186/s13046-019-1389-3.
12 Expression of serine peptidase inhibitor Kunitz type 1 in differentiated thyroid cancer.Histochem Cell Biol. 2018 Jun;149(6):635-644. doi: 10.1007/s00418-018-1660-2. Epub 2018 Mar 12.
13 The role of hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 in endometrial cancer.Int J Cancer. 2011 Jun 1;128(11):2613-24. doi: 10.1002/ijc.25606. Epub 2010 Oct 4.
14 Decreasing the ratio of matriptase/HAI? by downregulation of matriptase as a potential adjuvant therapy in ovarian cancer.Mol Med Rep. 2016 Aug;14(2):1465-74. doi: 10.3892/mmr.2016.5435. Epub 2016 Jun 23.
15 Decreased expression of SPINT1-AS1 and SPINT1 mRNA might be independent unfavorable prognostic indicators in esophageal squamous cell carcinoma.Onco Targets Ther. 2019 Jun 20;12:4755-4763. doi: 10.2147/OTT.S206448. eCollection 2019.
16 Expression of hepatocyte growth factor activator and hepatocyte growth factor activator inhibitor type 1 in human hepatocellular carcinoma.Biochem Biophys Res Commun. 2001 Nov 23;289(1):205-11. doi: 10.1006/bbrc.2001.5916.
17 Viral load speaks little about toll on liver.Hepatobiliary Pancreat Dis Int. 2007 Oct;6(5):483-6.
18 The impact of immunosenescence on humoral immune response variation after influenza A/H1N1 vaccination in older subjects.PLoS One. 2015 Mar 27;10(3):e0122282. doi: 10.1371/journal.pone.0122282. eCollection 2015.
19 Inhibition of nuclear factor-B signaling suppresses Spint1-deletion-induced tumor susceptibility in the ApcMin/+ model.Oncotarget. 2016 Oct 18;7(42):68614-68622. doi: 10.18632/oncotarget.11863.
20 Novel Role for -Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1).J Biol Chem. 2015 Jun 19;290(25):15610-15620. doi: 10.1074/jbc.M114.631820. Epub 2015 Apr 29.
21 Suppression of hepatocyte growth factor activator inhibitor-1 leads to a more aggressive phenotype of prostate cancer cells in vitro.Int J Mol Med. 2007 Oct;20(4):613-9.
22 Imbalance in the pro-hepatocyte growth factor activation system in bleomycin-induced lung fibrosis in mice.Am J Respir Cell Mol Biol. 2010 Mar;42(3):286-93. doi: 10.1165/rcmb.2008-0305OC. Epub 2009 May 15.
23 miR-221 and miR-222 synergistically regulate hepatocyte growth factor activator inhibitor type 1 to promote cell proliferation and migration in gastric cancer.Tumour Biol. 2017 Jun;39(6):1010428317701636. doi: 10.1177/1010428317701636.
24 Promoter Hypomethylation Is Responsible for Upregulated Expression of HAI-1 in Hepatocellular Carcinoma.Dis Markers. 2019 Aug 28;2019:9175215. doi: 10.1155/2019/9175215. eCollection 2019.
25 Augmented expression of hepatocytes growth factor activator inhibitor type 1 (HAI-1) in intrahepatic small bile ducts in primary biliary cirrhosis.Virchows Arch. 2006 Oct;449(4):462-71. doi: 10.1007/s00428-006-0257-7. Epub 2006 Aug 29.
26 Roles of Kunitz domains in the anti-invasive effect of hepatocyte growth factor activator inhibitor type 1 in human glioblastoma cells.Hum Cell. 2007 Nov;20(4):100-6. doi: 10.1111/j.1749-0774.2007.00035.x.
27 Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients.Hepatology. 2005 May;41(5):995-1003. doi: 10.1002/hep.20664.
28 Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) are potential targets in uterine leiomyosarcoma.Int J Oncol. 2010 Sep;37(3):605-14. doi: 10.3892/ijo_00000709.
29 Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer.J Clin Oncol. 2003 Feb 1;21(3):406-12. doi: 10.1200/JCO.2003.06.060.
30 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
31 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.
32 RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
33 Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
34 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
35 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.
36 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.
37 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.
38 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.
39 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.
40 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.
41 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.