Details of Drug Off-Target (DOT)

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

DOT Name Dickkopf-related protein 1 (DKK1)
Synonyms Dickkopf-1; Dkk-1; hDkk-1; SK
Gene Name DKK1
UniProt ID
DKK1_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
3S2K; 3S8V; 3SOQ; 5FWW; 5GJE
Pfam ID
PF04706 ; PF21481 ; PF21479
Sequence
MMALGAAGATRVFVAMVAAALGGHPLLGVSATLNSVLNSNAIKNLPPPLGGAAGHPGSAV
SAAPGILYPGGNKYQTIDNYQPYPCAEDEECGTDEYCASPTRGGDAGVQICLACRKRRKR
CMRHAMCCPGNYCKNGICVSSDQNHFRGEIEETITESFGNDHSTLDGYSRRTTLSSKMYH
TKGQEGSVCLRSSDCASGLCCARHFWSKICKPVLKEGQVCTKHRRKGSHGLEIFQRCYCG
EGLSCRIQKDHHQASNSSRLHTCQRH
Function
Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease. Inhibits the pro-apoptotic function of KREMEN1 in a Wnt-independent manner, and has anti-apoptotic activity.
Tissue Specificity Placenta.
KEGG Pathway
Wnt sig.ling pathway (hsa04310 )
Alzheimer disease (hsa05010 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Reactome Pathway
Negative regulation of TCF-dependent signaling by WNT ligand antagonists (R-HSA-3772470 )
Signaling by LRP5 mutants (R-HSA-5339717 )
TCF dependent signaling in response to WNT (R-HSA-201681 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 6 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Dickkopf-related protein 1 (DKK1) affects the response to substance of Doxorubicin. [47]
Cisplatin DMRHGI9 Approved Dickkopf-related protein 1 (DKK1) affects the response to substance of Cisplatin. [47]
Methotrexate DM2TEOL Approved Dickkopf-related protein 1 (DKK1) decreases the response to substance of Methotrexate. [48]
DTI-015 DMXZRW0 Approved Dickkopf-related protein 1 (DKK1) increases the response to substance of DTI-015. [49]
Vinblastine DM5TVS3 Approved Dickkopf-related protein 1 (DKK1) affects the response to substance of Vinblastine. [47]
[3H]cAMP DMZRQU7 Investigative Dickkopf-related protein 1 (DKK1) affects the response to substance of [3H]cAMP. [50]
------------------------------------------------------------------------------------
⏷ Show the Full List of 6 Drug(s)
51 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 Dickkopf-related protein 1 (DKK1). [1]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Dickkopf-related protein 1 (DKK1). [2]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Dickkopf-related protein 1 (DKK1). [3]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Dickkopf-related protein 1 (DKK1). [4]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Dickkopf-related protein 1 (DKK1). [5]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Dickkopf-related protein 1 (DKK1). [2]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Dickkopf-related protein 1 (DKK1). [6]
Quercetin DM3NC4M Approved Quercetin decreases the expression of Dickkopf-related protein 1 (DKK1). [7]
Temozolomide DMKECZD Approved Temozolomide increases the expression of Dickkopf-related protein 1 (DKK1). [8]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Dickkopf-related protein 1 (DKK1). [9]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide increases the expression of Dickkopf-related protein 1 (DKK1). [10]
Triclosan DMZUR4N Approved Triclosan decreases the expression of Dickkopf-related protein 1 (DKK1). [11]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Dickkopf-related protein 1 (DKK1). [12]
Decitabine DMQL8XJ Approved Decitabine increases the expression of Dickkopf-related protein 1 (DKK1). [13]
Marinol DM70IK5 Approved Marinol decreases the expression of Dickkopf-related protein 1 (DKK1). [14]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Dickkopf-related protein 1 (DKK1). [15]
Progesterone DMUY35B Approved Progesterone increases the expression of Dickkopf-related protein 1 (DKK1). [16]
Menadione DMSJDTY Approved Menadione increases the expression of Dickkopf-related protein 1 (DKK1). [10]
Fluorouracil DMUM7HZ Approved Fluorouracil decreases the expression of Dickkopf-related protein 1 (DKK1). [17]
Dexamethasone DMMWZET Approved Dexamethasone increases the expression of Dickkopf-related protein 1 (DKK1). [18]
Folic acid DMEMBJC Approved Folic acid increases the expression of Dickkopf-related protein 1 (DKK1). [19]
Niclosamide DMJAGXQ Approved Niclosamide decreases the expression of Dickkopf-related protein 1 (DKK1). [20]
Hydroquinone DM6AVR4 Approved Hydroquinone affects the expression of Dickkopf-related protein 1 (DKK1). [21]
Azathioprine DMMZSXQ Approved Azathioprine decreases the expression of Dickkopf-related protein 1 (DKK1). [22]
Diclofenac DMPIHLS Approved Diclofenac affects the expression of Dickkopf-related protein 1 (DKK1). [12]
Dasatinib DMJV2EK Approved Dasatinib decreases the expression of Dickkopf-related protein 1 (DKK1). [23]
Methamphetamine DMPM4SK Approved Methamphetamine increases the expression of Dickkopf-related protein 1 (DKK1). [24]
Vitamin C DMXJ7O8 Approved Vitamin C decreases the expression of Dickkopf-related protein 1 (DKK1). [25]
Bexarotene DMOBIKY Approved Bexarotene increases the expression of Dickkopf-related protein 1 (DKK1). [26]
Ampicillin DMHWE7P Approved Ampicillin increases the expression of Dickkopf-related protein 1 (DKK1). [27]
Adenosine DMM2NSK Approved Adenosine increases the expression of Dickkopf-related protein 1 (DKK1). [28]
Letrozole DMH07Y3 Approved Letrozole increases the expression of Dickkopf-related protein 1 (DKK1). [29]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of Dickkopf-related protein 1 (DKK1). [30]
Dihydrotestosterone DM3S8XC Phase 4 Dihydrotestosterone increases the expression of Dickkopf-related protein 1 (DKK1). [31]
Genistein DM0JETC Phase 2/3 Genistein decreases the expression of Dickkopf-related protein 1 (DKK1). [32]
Belinostat DM6OC53 Phase 2 Belinostat increases the expression of Dickkopf-related protein 1 (DKK1). [33]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Dickkopf-related protein 1 (DKK1). [2]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Dickkopf-related protein 1 (DKK1). [34]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of Dickkopf-related protein 1 (DKK1). [35]
THAPSIGARGIN DMDMQIE Preclinical THAPSIGARGIN decreases the expression of Dickkopf-related protein 1 (DKK1). [36]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Dickkopf-related protein 1 (DKK1). [37]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Dickkopf-related protein 1 (DKK1). [38]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of Dickkopf-related protein 1 (DKK1). [39]
Acetaldehyde DMJFKG4 Investigative Acetaldehyde decreases the expression of Dickkopf-related protein 1 (DKK1). [41]
Glyphosate DM0AFY7 Investigative Glyphosate decreases the expression of Dickkopf-related protein 1 (DKK1). [42]
Nickel chloride DMI12Y8 Investigative Nickel chloride increases the expression of Dickkopf-related protein 1 (DKK1). [9]
Phencyclidine DMQBEYX Investigative Phencyclidine decreases the expression of Dickkopf-related protein 1 (DKK1). [43]
Tributylstannanyl DMHN7CB Investigative Tributylstannanyl decreases the expression of Dickkopf-related protein 1 (DKK1). [44]
U0126 DM31OGF Investigative U0126 decreases the expression of Dickkopf-related protein 1 (DKK1). [45]
BRN-3548355 DM4KXT0 Investigative BRN-3548355 increases the expression of Dickkopf-related protein 1 (DKK1). [46]
Benzoquinone DMNBA0G Investigative Benzoquinone increases the expression of Dickkopf-related protein 1 (DKK1). [21]
------------------------------------------------------------------------------------
⏷ Show the Full List of 51 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Sulforaphane DMQY3L0 Investigative Sulforaphane increases the methylation of Dickkopf-related protein 1 (DKK1). [40]
------------------------------------------------------------------------------------

References

1 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
2 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.
3 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
4 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
5 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
6 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.
7 Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
8 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.
9 Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
10 Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
11 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
12 Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
13 Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. Clin Cancer Res. 2007 Sep 1;13(17):5219-25. doi: 10.1158/1078-0432.CCR-07-0816.
14 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.
15 Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
16 Dickkopf-1, an inhibitor of Wnt signaling, is regulated by progesterone in human endometrial stromal cells. J Clin Endocrinol Metab. 2006 Apr;91(4):1453-61. doi: 10.1210/jc.2005-0769. Epub 2006 Jan 31.
17 Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
18 Dickkopf 1 mediates glucocorticoid-induced changes in human neural progenitor cell proliferation and differentiation. Toxicol Sci. 2012 Feb;125(2):488-95. doi: 10.1093/toxsci/kfr304. Epub 2011 Nov 1.
19 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.
20 Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
21 How benzene and its metabolites affect human marrow derived mesenchymal stem cells. Toxicol Lett. 2012 Oct 17;214(2):145-53. doi: 10.1016/j.toxlet.2012.08.015. Epub 2012 Aug 30.
22 A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
23 Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
24 Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
25 Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
26 Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
27 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.
28 Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/-Catenin Pathway Stimulation by Regulating GSK3b Activity. Int J Mol Sci. 2021 May 25;22(11):5571. doi: 10.3390/ijms22115571.
29 Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome. Fertil Steril. 2011 Oct;96(4):1051-6. doi: 10.1016/j.fertnstert.2011.07.1092.
30 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
31 L-ascorbic acid 2-phosphate represses the dihydrotestosterone-induced dickkopf-1 expression in human balding dermal papilla cells. Exp Dermatol. 2010 Dec;19(12):1110-2. doi: 10.1111/j.1600-0625.2010.01143.x.
32 Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
33 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.
34 Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
35 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
36 Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
37 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.
38 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.
39 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
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 In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
42 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.
43 Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
44 Persistent organic pollutants alter DNA methylation during human adipocyte differentiation. Toxicol In Vitro. 2017 Apr;40:79-87. doi: 10.1016/j.tiv.2016.12.011. Epub 2016 Dec 20.
45 Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
46 Tobacco nitrosamine NNK increases ALDH-positive cells via ROS-Wnt signaling pathway in A549 human lung cancer cells. J Toxicol Sci. 2017;42(2):193-204. doi: 10.2131/jts.42.193.
47 Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
48 Networking of differentially expressed genes in human cancer cells resistant to methotrexate. Genome Med. 2009 Sep 4;1(9):83. doi: 10.1186/gm83.
49 Elevated expression of Dickkopf-1 increases the sensitivity of human glioma cell line SHG44 to BCNU. J Exp Clin Cancer Res. 2010 Oct 4;29(1):131. doi: 10.1186/1756-9966-29-131.
50 Prokineticin 1 induces Dickkopf 1 expression and regulates cell proliferation and decidualization in the human endometrium. Mol Hum Reprod. 2011 Oct;17(10):626-36. doi: 10.1093/molehr/gar031. Epub 2011 May 5.