Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDU94EY)

• DOT Name: Dickkopf-related protein 3 (DKK3)
• Synonyms: Dickkopf-3; Dkk-3; hDkk-3
• Gene Name: DKK3
• UniProt ID: DKK3_HUMAN
• Pfam ID: PF04706
• Sequence:
  MQRLGATLLCLLLAAAVPTAPAPAPTATSAPVKPGPALSYPQEEATLNEMFREVEELMED
  TQHKLRSAVEEMEAEEAAAKASSEVNLANLPPSYHNETNTDTKVGNNTIHVHREIHKITN
  NQTGQMVFSETVITSVGDEEGRRSHECIIDEDCGPSMYCQFASFQYTCQPCRGQRMLCTR
  DSECCGDQLCVWGHCTKMATRGSNGTICDNQRDCQPGLCCAFQRGLLFPVCTPLPVEGEL
  CHDPASRLLDLITWELEPDGALDRCPCASGLLCQPHSHSLVYVCKPTFVGSRDQDGEILL
  PREVPDEYEVGSFMEEVRQELEDLERSLTEEMALREPAAAAAALLGGEEI
• 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.
• Tissue Specificity: Highest expression in heart, brain, and spinal cord.

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Dickkopf-related protein 3 (DKK3) affects the response to substance of Etoposide.	[20]
Mitomycin	DMH0ZJE	Approved	Dickkopf-related protein 3 (DKK3) affects the response to substance of Mitomycin.	[20]
Topotecan	DMP6G8T	Approved	Dickkopf-related protein 3 (DKK3) affects the response to substance of Topotecan.	[20]
Vinblastine	DM5TVS3	Approved	Dickkopf-related protein 3 (DKK3) affects the response to substance of Vinblastine.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Dickkopf-related protein 3 (DKK3).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dickkopf-related protein 3 (DKK3).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Dickkopf-related protein 3 (DKK3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dickkopf-related protein 3 (DKK3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dickkopf-related protein 3 (DKK3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dickkopf-related protein 3 (DKK3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dickkopf-related protein 3 (DKK3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dickkopf-related protein 3 (DKK3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Dickkopf-related protein 3 (DKK3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dickkopf-related protein 3 (DKK3).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dickkopf-related protein 3 (DKK3).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dickkopf-related protein 3 (DKK3).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Dickkopf-related protein 3 (DKK3).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Dickkopf-related protein 3 (DKK3).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Dickkopf-related protein 3 (DKK3).	[12]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Dickkopf-related protein 3 (DKK3).	[14]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Dickkopf-related protein 3 (DKK3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dickkopf-related protein 3 (DKK3).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dickkopf-related protein 3 (DKK3).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Dickkopf-related protein 3 (DKK3).	[19]

References

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• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
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• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] 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.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] Progesterone rise on HCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. Reprod Biomed Online. 2011 Mar;22(3):263-71. doi: 10.1016/j.rbmo.2010.11.002. Epub 2010 Nov 13.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
• [15] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] 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.