Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5QBTA4)

• DOT Name: Nicastrin (NCSTN)
• Gene Name: NCSTN
• Related Disease:
  Neuroblastoma
  Acne inversa, familial, 1
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Dementia
  Familial acne inversa
  Hepatocellular carcinoma
  Hidradenitis suppurativa
  Schizophrenia
  Skin disease
  Advanced cancer
  Invasive breast carcinoma
  Pancreatic cancer
  Alzheimer disease
  Familial Alzheimer disease
  Inflammation
  Neoplasm
  Parkinson disease
• UniProt ID: NICA_HUMAN
• PDB ID: 2N7Q; 2N7R; 4UIS; 5A63; 5FN2; 5FN3; 5FN4; 5FN5; 6IDF; 6IYC; 6LQG; 6LR4; 7C9I; 7D8X; 7Y5T; 7Y5X; 7Y5Z
• Pfam ID: PF18266 ; PF05450
• Sequence:
  MATAGGGSGADPGSRGLLRLLSFCVLLAGLCRGNSVERKIYIPLNKTAPCVRLLNATHQI
  GCQSSISGDTGVIHVVEKEEDLQWVLTDGPNPPYMVLLESKHFTRDLMEKLKGRTSRIAG
  LAVSLTKPSPASGFSPSVQCPNDGFGVYSNSYGPEFAHCREIQWNSLGNGLAYEDFSFPI
  FLLEDENETKVIKQCYQDHNLSQNGSAPTFPLCAMQLFSHMHAVISTATCMRRSSIQSTF
  SINPEIVCDPLSDYNVWSMLKPINTTGTLKPDDRVVVAATRLDSRSFFWNVAPGAESAVA
  SFVTQLAAAEALQKAPDVTTLPRNVMFVFFQGETFDYIGSSRMVYDMEKGKFPVQLENVD
  SFVELGQVALRTSLELWMHTDPVSQKNESVRNQVEDLLATLEKSGAGVPAVILRRPNQSQ
  PLPPSSLQRFLRARNISGVVLADHSGAFHNKYYQSIYDTAENINVSYPEWLSPEEDLNFV
  TDTAKALADVATVLGRALYELAGGTNFSDTVQADPQTVTRLLYGFLIKANNSWFQSILRQ
  DLRSYLGDGPLQHYIAVSSPTNTTYVVQYALANLTGTVVNLTREQCQDPSKVPSENKDLY
  EYSWVQGPLHSNETDRLPRCVRSTARLARALSPAFELSQWSSTEYSTWTESRWKDIRARI
  FLIASKELELITLTVGFGILIFSLIVTYCINAKADVLFIAPREPGAVSY
• Function: Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels.
• Tissue Specificity: Detected in brain (at protein level) . Widely expressed .
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Alzheimer disease (hsa05010)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Neutrophil degranulation (R-HSA-6798695)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  NOTCH4 Activation and Transmission of Signal to the Nucleus (R-HSA-9013700)
  Noncanonical activation of NOTCH3 (R-HSA-9017802)
  Amyloid fiber formation (R-HSA-977225)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Acne inversa, familial, 1	DISPK28T	Strong	Autosomal dominant	[2]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Dementia	DISXL1WY	Strong	Genetic Variation	[5]
Familial acne inversa	DIS7DVKA	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Hidradenitis suppurativa	DIS3ZNAK	Strong	Genetic Variation	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Skin disease	DISDW8R6	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[10]
Invasive breast carcinoma	DISANYTW	moderate	Biomarker	[11]
Pancreatic cancer	DISJC981	moderate	Biomarker	[12]
Alzheimer disease	DISF8S70	Limited	Biomarker	[13]
Familial Alzheimer disease	DISE75U4	Limited	Biomarker	[14]
Inflammation	DISJUQ5T	Limited	Biomarker	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[16]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Nicastrin (NCSTN) affects the response to substance of Irinotecan.	[29]

12 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 Nicastrin (NCSTN).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nicastrin (NCSTN).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nicastrin (NCSTN).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nicastrin (NCSTN).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nicastrin (NCSTN).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of Nicastrin (NCSTN).	[22]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Nicastrin (NCSTN).	[23]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Nicastrin (NCSTN).	[24]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Nicastrin (NCSTN).	[25]
Isoflurane	DMY6T31	Approved	Isoflurane increases the expression of Nicastrin (NCSTN).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nicastrin (NCSTN).	[27]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Nicastrin (NCSTN).	[28]

References

• [1] Changes in cholesterol metabolism are associated with PS1 and PS2 gene regulation in SK-N-BE.J Mol Neurosci. 2006;30(3):311-22. doi: 10.1385/JMN:30:3:311.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Age- and sex-dependent profiles of APP fragments and key secretases align with changes in despair-like behavior and cognition in young APPSwe/Ind mice.Biochem Biophys Res Commun. 2019 Apr 2;511(2):454-459. doi: 10.1016/j.bbrc.2019.02.083. Epub 2019 Feb 22.
• [4] Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells.Breast Cancer Res. 2014 Jun 11;16(3):R62. doi: 10.1186/bcr3675.
• [5] Nicastrin gene polymorphisms, cognitive ability level and cognitive ageing.Neurosci Lett. 2005 Jan 10;373(2):110-4. doi: 10.1016/j.neulet.2004.09.073.
• [6] Nicastrin/miR-30a-3p/RAB31 Axis Regulates Keratinocyte Differentiation by Impairing EGFR Signaling in Familial Acne Inversa.J Invest Dermatol. 2019 Jan;139(1):124-134. doi: 10.1016/j.jid.2018.07.020. Epub 2018 Aug 16.
• [7] Identification of potential driver genes in human liver carcinoma by genomewide screening.Cancer Res. 2009 May 1;69(9):4059-66. doi: 10.1158/0008-5472.CAN-09-0164. Epub 2009 Apr 14.
• [8] A novel NCSTN gene mutation in a Chinese family with acne inversa.Mol Genet Genomics. 2018 Dec;293(6):1469-1475. doi: 10.1007/s00438-018-1475-9. Epub 2018 Jul 20.
• [9] Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior.J Biol Chem. 2016 May 27;291(22):11647-56. doi: 10.1074/jbc.M116.715078. Epub 2016 Mar 23.
• [10] The role of polycomb group protein Bmi-1 and Notch4 in breast cancer stem cell inhibition by benzyl isothiocyanate.Breast Cancer Res Treat. 2015 Feb;149(3):681-92. doi: 10.1007/s10549-015-3279-5. Epub 2015 Feb 8.
• [11] The role of genes co-amplified with nicastrin in breast invasive carcinoma.Breast Cancer Res Treat. 2014 Jan;143(2):393-401. doi: 10.1007/s10549-013-2805-6. Epub 2013 Dec 13.
• [12] Evaluation of the prognostic significances of -secretase genes in pancreatic cancer.Oncol Lett. 2019 May;17(5):4614-4620. doi: 10.3892/ol.2019.10113. Epub 2019 Mar 5.
• [13] Enhanced amyloid- generation by -secretase complex in DRM microdomains with reduced cholesterol levels.Hum Mol Genet. 2020 Feb 1;29(3):382-393. doi: 10.1093/hmg/ddz297.
• [14] Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.Nat Genet. 2007 Jan;39(1):17-23. doi: 10.1038/ng1934.
• [15] Hidradenitis Suppurativa: A Systematic Review Integrating Inflammatory Pathways Into a Cohesive Pathogenic Model.Front Immunol. 2018 Dec 14;9:2965. doi: 10.3389/fimmu.2018.02965. eCollection 2018.
• [16] Cerebrospinal fluid A42 levels and APP processing pathway genes in Parkinson's disease.Mov Disord. 2015 Jun;30(7):936-44. doi: 10.1002/mds.26172. Epub 2015 Mar 24.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [25] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [26] The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci. 2007 Feb 7;27(6):1247-54. doi: 10.1523/JNEUROSCI.5320-06.2007.
• [27] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [28] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [29] gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res. 2009 Jan 15;69(2):573-82. doi: 10.1158/0008-5472.CAN-08-2088.