Details of Drug Off-Target (DOT)

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

• DOT Name: Trypsin-2 (PRSS2)
• Synonyms: EC 3.4.21.4; Anionic trypsinogen; Serine protease 2; Trypsin II
• Gene Name: PRSS2
• Related Disease:
  Advanced cancer
  Anaplastic large cell lymphoma
  Bronchopulmonary dysplasia
  Cholangiocarcinoma
  Diabetic kidney disease
  Esophageal squamous cell carcinoma
  Hereditary chronic pancreatitis
  Matthew-Wood syndrome
  Pancreas disorder
  Primary hyperparathyroidism
  Prostate neoplasm
  Sporotrichosis
  Squamous cell carcinoma
  Epithelial ovarian cancer
  Rheumatoid arthritis
  Synovitis
  Tropical pancreatitis
  Type 2 collagenopathy
  Colonic neoplasm
  Colorectal carcinoma
  Lewy body dementia
  Neoplasm
  Pancreatic cancer
  Parkinson disease
  Patent ductus arteriosus
  Pneumonia
  Psychotic disorder
• UniProt ID: TRY2_HUMAN
• EC Number: 3.4.21.4
• Pfam ID: PF00089
• Sequence:
  MNLLLILTFVAAAVAAPFDDDDKIVGGYICEENSVPYQVSLNSGYHFCGGSLISEQWVVS
  AGHCYKSRIQVRLGEHNIEVLEGNEQFINAAKIIRHPKYNSRTLDNDILLIKLSSPAVIN
  SRVSAISLPTAPPAAGTESLISGWGNTLSSGADYPDELQCLDAPVLSQAECEASYPGKIT
  NNMFCVGFLEGGKDSCQGDSGGPVVSNGELQGIVSWGYGCAQKNRPGVYTKVYNYVDWIK
  DTIAANS
• Function: In the ileum, may be involved in defensin processing, including DEFA5.
• Tissue Specificity: Expressed in Paneth cells, at the base of small intestinal crypts.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Pancreatic secretion (hsa04972)
  Protein digestion and absorption (hsa04974)
  Influenza A (hsa05164)
• Reactome Pathway:
  Alpha-defensins (R-HSA-1462054)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Neutrophil degranulation (R-HSA-6798695)
  Antimicrobial peptides (R-HSA-6803157)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[2]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Altered Expression	[3]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[4]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Hereditary chronic pancreatitis	DISF0J1Q	Strong	Genetic Variation	[7]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[8]
Pancreas disorder	DISDH7NI	Strong	Altered Expression	[9]
Primary hyperparathyroidism	DISB4U1Q	Strong	Genetic Variation	[10]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[11]
Sporotrichosis	DISZA6J9	Strong	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[13]
Rheumatoid arthritis	DISTSB4J	moderate	Biomarker	[14]
Synovitis	DISW2GPY	moderate	Altered Expression	[14]
Tropical pancreatitis	DIS3OT4T	moderate	Genetic Variation	[15]
Type 2 collagenopathy	DIS8WIDY	moderate	Biomarker	[14]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[16]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[16]
Lewy body dementia	DISAE66J	Limited	Altered Expression	[17]
Neoplasm	DISZKGEW	Limited	Biomarker	[18]
Pancreatic cancer	DISJC981	Limited	Biomarker	[19]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[17]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[20]
Pneumonia	DIS8EF3M	Limited	Biomarker	[21]
Psychotic disorder	DIS4UQOT	Limited	Altered Expression	[17]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Trypsin-2 (PRSS2).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Trypsin-2 (PRSS2).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Trypsin-2 (PRSS2).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the expression of Trypsin-2 (PRSS2).	[25]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Trypsin-2 (PRSS2).	[26]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Trypsin-2 (PRSS2).	[27]
Vandetanib	DMRICNP	Approved	Vandetanib increases the expression of Trypsin-2 (PRSS2).	[28]

References

• [1] Intracellular co-localization of trypsin-2 and matrix metalloprotease-9: possible proteolytic cascade of trypsin-2, MMP-9 and enterokinase in carcinoma.Exp Cell Res. 2008 Feb 15;314(4):914-26. doi: 10.1016/j.yexcr.2007.10.025. Epub 2007 Nov 12.
• [2] Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines.Mol Cancer. 2008 Jan 7;7:2. doi: 10.1186/1476-4598-7-2.
• [3] Pulmonary trypsin-2 in the development of bronchopulmonary dysplasia in preterm infants.Pediatrics. 2003 Sep;112(3 Pt 1):570-7. doi: 10.1542/peds.112.3.570.
• [4] Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures.J Hepatol. 2007 Nov;47(5):677-83. doi: 10.1016/j.jhep.2007.05.017. Epub 2007 Jun 27.
• [5] Urinary matrix metalloproteinase -8, -9, -14 and their regulators (TRY-1, TRY-2, TATI) in patients with diabetic nephropathy.Ann Med. 2008;40(4):312-20. doi: 10.1080/07853890801923746.
• [6] Clinical significance of mannose-binding lectin-associated serine protease-2 expression in esophageal squamous cell carcinoma.Int J Cancer. 2006 Jun 15;118(12):2930-5. doi: 10.1002/ijc.21721.
• [7] Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis.J Biol Chem. 2016 Jun 17;291(25):12897-905. doi: 10.1074/jbc.M116.725374. Epub 2016 Apr 18.
• [8] Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation.Int J Cancer. 2018 Jan 15;142(2):290-296. doi: 10.1002/ijc.31047. Epub 2017 Oct 16.
• [9] Human anionic trypsinogen: properties of autocatalytic activation and degradation and implications in pancreatic diseases.Eur J Biochem. 2003 May;270(9):2047-58. doi: 10.1046/j.1432-1033.2003.03581.x.
• [10] Multifactorial genesis of pancreatitis in primary hyperparathyroidism: evidence for "protective" (PRSS2) and "destructive" (CTRC) genetic factors.Exp Clin Endocrinol Diabetes. 2011 Jan;119(1):26-9. doi: 10.1055/s-0030-1255106. Epub 2010 Jul 12.
• [11] Expression of tumor-associated trypsinogens (TAT-1 and TAT-2) in prostate cancer.Prostate. 2005 Jun 15;64(1):29-39. doi: 10.1002/pros.20236.
• [12] Mannose-Binding Lectin and Mannose-Binding Lectin-Associated Serine Protease-2 Genotypes and Serum Levels in Patients with Sporotrichosis.Am J Trop Med Hyg. 2019 Dec;101(6):1322-1324. doi: 10.4269/ajtmh.19-0470.
• [13] Expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor in ovarian cancer: prognostic study on tissue and serum.Clin Cancer Res. 2004 Jul 15;10(14):4761-8. doi: 10.1158/1078-0432.CCR-0204-03.
• [14] Trypsin-2 degrades human type II collagen and is expressed and activated in mesenchymally transformed rheumatoid arthritis synovitis tissue.Am J Pathol. 2005 Oct;167(4):1119-24. doi: 10.1016/S0002-9440(10)61200-X.
• [15] Divergent roles of SPINK1 and PRSS2 variants in tropical calcific pancreatitis.Pancreatology. 2009;9(1-2):145-9. doi: 10.1159/000178885. Epub 2008 Dec 13.
• [16] Human trypsinogen in colorectal cancer.Int J Cancer. 2001 Jul 1;93(1):67-73. doi: 10.1002/ijc.1304.
• [17] Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson's Disease.J Mol Neurosci. 2015 Sep;57(1):48-62. doi: 10.1007/s12031-015-0576-8. Epub 2015 May 17.
• [18] Trypsin-2 enhances carcinoma invasion by processing tight junctions and activating ProMT1-MMP.Cancer Invest. 2012 Oct;30(8):583-92. doi: 10.3109/07357907.2012.716467. Epub 2012 Aug 21.
• [19] Bioinformatics Tools and Workflow to Select Blood Biomarkers for Early Cancer Diagnosis: An Application to Pancreatic Cancer.Proteomics. 2019 Nov;19(21-22):e1800489. doi: 10.1002/pmic.201800489. Epub 2019 Oct 10.
• [20] Altered plasma proteins released from platelets and endothelial cells are associated with human patent ductus arteriosus.J Cell Physiol. 2019 May;234(5):6842-6853. doi: 10.1002/jcp.27433. Epub 2018 Nov 27.
• [21] Mannose-binding lectin and mannose-binding lectin-associated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults.J Allergy Clin Immunol. 2008 Aug;122(2):368-74, 374.e1-2. doi: 10.1016/j.jaci.2008.05.037. Epub 2008 Jun 25.
• [22] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [23] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [24] 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.
• [25] Time-series analysis in imatinib-resistant chronic myeloid leukemia K562-cells under different drug treatments. J Huazhong Univ Sci Technolog Med Sci. 2017 Aug;37(4):621-627. doi: 10.1007/s11596-017-1781-1. Epub 2017 Aug 8.
• [26] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [27] 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.
• [28] ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. Int J Cancer. 2006 Jan 15;118(2):483-9. doi: 10.1002/ijc.21340.