Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSUVAL2)

• DOT Name: Serine protease inhibitor Kazal-type 1 (SPINK1)
• Synonyms: Pancreatic secretory trypsin inhibitor; Tumor-associated trypsin inhibitor; TATI
• Gene Name: SPINK1
• Related Disease:
  Ovarian cancer
  Acute intermittent hepatic porphyria
  Acute myelogenous leukaemia
  Adenocarcinoma
  Advanced cancer
  Bladder cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Citrullinemia type II
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Cystic fibrosis
  Ductal carcinoma
  Epithelial ovarian cancer
  Exocrine pancreatic insufficiency
  Hereditary chronic pancreatitis
  Lymphoma
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Obesity
  Osteosarcoma
  Ovarian neoplasm
  Pancreas disorder
  Pancreatic tumour
  Primary hyperparathyroidism
  Renal cell carcinoma
  Tropical pancreatitis
  Type-1 diabetes
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vibrio cholerae infection
  Carcinoma
  Colorectal adenocarcinoma
  Hepatitis B virus infection
  Liver cirrhosis
  Lung adenocarcinoma
  Neoplasm
  Squamous cell carcinoma
  Hypercalcaemia
  Neuroblastoma
  Pancreatic adenocarcinoma
  Prostate neoplasm
• UniProt ID: ISK1_HUMAN
• PDB ID: 1CGI; 1CGJ; 1HPT; 7QE8; 7QE9
• Pfam ID: PF00050
• Sequence:
  MKVTGIFLLSALALLSLSGNTGADSLGREAKCYNELNGCTKIYDPVCGTDGNTYPNECVL
  CFENRKRQTSILIQKSGPC
• Function: Serine protease inhibitor which exhibits anti-trypsin activity. In the pancreas, protects against trypsin-catalyzed premature activation of zymogens; In the male reproductive tract, binds to sperm heads where it modulates sperm capacitance by inhibiting calcium uptake and nitrogen oxide (NO) production.

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[1]
Acute intermittent hepatic porphyria	DIS80J7E	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Citrullinemia type II	DIS2UURN	Strong	Altered Expression	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Altered Expression	[10]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[11]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[12]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[13]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[14]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Exocrine pancreatic insufficiency	DISCZYU2	Strong	Biomarker	[15]
Hereditary chronic pancreatitis	DISF0J1Q	Strong	Autosomal dominant	[16]
Lymphoma	DISN6V4S	Strong	Altered Expression	[17]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[18]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[20]
Obesity	DIS47Y1K	Strong	Biomarker	[21]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Pancreas disorder	DISDH7NI	Strong	Biomarker	[22]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[23]
Primary hyperparathyroidism	DISB4U1Q	Strong	Genetic Variation	[24]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[9]
Tropical pancreatitis	DIS3OT4T	Strong	Autosomal dominant	[25]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[26]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[27]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[28]
Carcinoma	DISH9F1N	moderate	Altered Expression	[29]
Colorectal adenocarcinoma	DISPQOUB	moderate	Genetic Variation	[11]
Hepatitis B virus infection	DISLQ2XY	moderate	Biomarker	[30]
Liver cirrhosis	DIS4G1GX	moderate	Altered Expression	[30]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[31]
Neoplasm	DISZKGEW	Disputed	Biomarker	[6]
Squamous cell carcinoma	DISQVIFL	Disputed	Biomarker	[32]
Hypercalcaemia	DISKQ2K7	Limited	Genetic Variation	[33]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[34]
Pancreatic adenocarcinoma	DISKHX7S	Limited	Genetic Variation	[35]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[36]

17 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 Serine protease inhibitor Kazal-type 1 (SPINK1).	[37]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[40]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[42]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[43]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[44]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[45]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[46]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[47]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[48]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[49]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[50]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[51]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[52]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine protease inhibitor Kazal-type 1 (SPINK1).	[53]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine protease inhibitor Kazal-type 1 (SPINK1).	[41]

References

• [1] Emerging Roles of SPINK1 in Cancer.Clin Chem. 2016 Mar;62(3):449-57. doi: 10.1373/clinchem.2015.241513. Epub 2015 Dec 11.
• [2] Human cationic trypsinogen but not serine peptidase inhibitor, Kazal type 1 variants increase the risk of type 1 autoimmune pancreatitis.J Gastroenterol Hepatol. 2014 Dec;29(12):2038-42. doi: 10.1111/jgh.12649.
• [3] LSD1/KDM1A inhibitors in clinical trials: advances and prospects.J Hematol Oncol. 2019 Dec 4;12(1):129. doi: 10.1186/s13045-019-0811-9.
• [4] RNA-seq analysis of lung adenocarcinomas reveals different gene expression profiles between smoking and nonsmoking patients.Tumour Biol. 2015 Nov;36(11):8993-9003. doi: 10.1007/s13277-015-3576-y. Epub 2015 Jun 17.
• [5] Prognostic value of the combined expression of tumor-associated trypsin inhibitor (TATI) and p53 in patients with bladder cancer undergoing radical cystectomy.Cancer Biomark. 2019;26(3):281-289. doi: 10.3233/CBM-182143.
• [6] A novel multifunctional carbon aerogel-coated platform for osteosarcoma therapy and enhanced bone regeneration.J Mater Chem B. 2020 Jan 22;8(3):368-379. doi: 10.1039/c9tb02383f.
• [7] Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer.EMBO Mol Med. 2011 Aug;3(8):451-64. doi: 10.1002/emmm.201100150. Epub 2011 Jun 8.
• [8] Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate.J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S343-7. doi: 10.1007/s10545-008-0914-x. Epub 2008 Oct 29.
• [9] Tumor-associated trypsin inhibitor in normal and malignant renal tissue and in serum of renal-cell carcinoma patients.Int J Cancer. 1999 Nov 12;83(4):486-90. doi: 10.1002/(sici)1097-0215(19991112)83:4<486::aid-ijc9>3.0.co;2-o.
• [10] Interleukin-6 increases expression of serine protease inhibitor Kazal type 1 through STAT3 in colorectal adenocarcinoma.Mol Carcinog. 2016 Dec;55(12):2010-2023. doi: 10.1002/mc.22447. Epub 2015 Dec 14.
• [11] MAPK inhibitors induce serine peptidase inhibitor Kazal type 1 (SPINK1) secretion in BRAF V600E-mutant colorectal adenocarcinoma.Mol Oncol. 2018 Feb;12(2):224-238. doi: 10.1002/1878-0261.12160. Epub 2017 Dec 27.
• [12] Co-expression of trypsin and tumour-associated trypsin inhibitor (TATI) in colorectal adenocarcinomas.Histol Histopathol. 2003 Oct;18(4):1181-8. doi: 10.14670/HH-18.1181.
• [13] Hereditary pancreatitis of 3 Chinese children: Case report and literature review.Medicine (Baltimore). 2016 Sep;95(36):e4604. doi: 10.1097/MD.0000000000004604.
• [14] Clinical significance and EZH2, ERG and SPINK1 protein expression in pure and mixed ductal adenocarcinoma of the prostate.Histol Histopathol. 2019 Apr;34(4):381-390. doi: 10.14670/HH-18-046. Epub 2018 Sep 24.
• [15] Natural history of SPINK1 germline mutation related-pancreatitis.EBioMedicine. 2019 Oct;48:581-591. doi: 10.1016/j.ebiom.2019.09.032. Epub 2019 Oct 15.
• [16] The child with epilepsy. Teaching children about their seizures and medications. MCN Am J Matern Child Nurs. 1979 May-Jun;4(3):161-2. doi: 10.1097/00005721-197905000-00006.
• [17] Expression of pancreatic secretory trypsin inhibitor gene in human colorectal tumor.Cancer. 1990 Nov 15;66(10):2144-9. doi: 10.1002/1097-0142(19901115)66:10<2144::aid-cncr2820661017>3.0.co;2-#.
• [18] Common SPINK-1 mutations do not predispose to the development of non-alcoholic fatty liver disease.Ann Hepatol. 2009 Apr-Jun;8(2):116-9.
• [19] The SPINK1 N34S mutation is not associated with Type 2 diabetes mellitus in a population of the USA.Diabet Med. 2005 Jun;22(6):744-8. doi: 10.1111/j.1464-5491.2005.01513.x.
• [20] SPINK1 is a prognosis predicting factor of non-small cell lung cancer and regulates redox homeostasis.Oncol Lett. 2019 Dec;18(6):6899-6908. doi: 10.3892/ol.2019.11005. Epub 2019 Oct 18.
• [21] Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease.J Hepatol. 2008 Nov;49(5):810-20. doi: 10.1016/j.jhep.2008.05.016. Epub 2008 Jun 10.
• [22] Roles of serine protease inhibitor Kazal type 1 (SPINK1) in pancreatic diseases.Exp Anim. 2011;60(5):433-44. doi: 10.1538/expanim.60.433.
• [23] Chronic pancreatitis and pancreatic cancer: prediction and mechanism.Clin Gastroenterol Hepatol. 2009 Nov;7(11 Suppl):S23-8. doi: 10.1016/j.cgh.2009.07.042.
• [24] 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.
• [25] Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000 Jun;25(2):213-6. doi: 10.1038/76088.
• [26] Characterization of two deletions of the CTRC locus.Mol Genet Metab. 2013 Jul;109(3):296-300. doi: 10.1016/j.ymgme.2013.04.022. Epub 2013 May 10.
• [27] The contribution of the SPINK1 c.194+2T>C mutation to the clinical course of idiopathic chronic pancreatitis in Chinese patients.Dig Liver Dis. 2013 Jan;45(1):38-42. doi: 10.1016/j.dld.2012.08.008. Epub 2012 Sep 25.
• [28] Regulation by ToxR-Like Proteins Converges on vttRB Expression To Control Type 3 Secretion System-Dependent Caco2-BBE Cytotoxicity in Vibrio cholerae.J Bacteriol. 2016 May 13;198(11):1675-1682. doi: 10.1128/JB.00130-16. Print 2016 Jun 1.
• [29] Pancreatic secretory trypsin inhibitor causes autocrine-mediated migration and invasion in bladder cancer and phosphorylates the EGF receptor, Akt2 and Akt3, and ERK1 and ERK2.Am J Physiol Renal Physiol. 2013 Aug 1;305(3):F382-9. doi: 10.1152/ajprenal.00357.2012. Epub 2013 May 22.
• [30] Hepatitis B Virus X Protein-Induced Serine Protease Inhibitor Kazal Type 1 Is Associated with the Progression of HBV-Related Diseases.Biomed Res Int. 2019 May 22;2019:9321494. doi: 10.1155/2019/9321494. eCollection 2019.
• [31] SPINK1 promotes cell growth and metastasis of lung adenocarcinoma and acts as a novel prognostic biomarker.BMB Rep. 2018 Dec;51(12):648-653. doi: 10.5483/BMBRep.2018.51.12.205.
• [32] Integrated molecular portrait of non-small cell lung cancers.BMC Med Genomics. 2013 Dec 3;6:53. doi: 10.1186/1755-8794-6-53.
• [33] Cinacalcet sustainedly prevents pancreatitis in a child with a compound heterozygous SPINK1/AP2S1 mutation.Pancreatology. 2019 Sep;19(6):801-804. doi: 10.1016/j.pan.2019.07.045. Epub 2019 Jul 30.
• [34] Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway.Oncogene. 2017 Nov 30;36(48):6701-6711. doi: 10.1038/onc.2017.267. Epub 2017 Aug 7.
• [35] CFTR, SPINK1, PRSS1, and CTRC mutations are not associated with pancreatic cancer in German patients.Pancreas. 2014 Oct;43(7):1078-82. doi: 10.1097/MPA.0000000000000166.
• [36] Integrative molecular profiling of routine clinical prostate cancer specimens.Ann Oncol. 2015 Jun;26(6):1110-1118. doi: 10.1093/annonc/mdv134. Epub 2015 Mar 3.
• [37] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [38] 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.
• [39] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [40] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [41] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [42] 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.
• [43] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [44] 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.
• [45] 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.
• [46] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [47] High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells. Br J Nutr. 2008 Apr;99(4):703-8.
• [48] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [49] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [50] Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. 2017 Jul;37(7):863-872. doi: 10.1002/jat.3435. Epub 2017 Jan 31.
• [51] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [52] 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.
• [53] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.