Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBCPII8)

• DOT Name: Frizzled-6 (FZD6)
• Synonyms: Fz-6; hFz6
• Gene Name: FZD6
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Obsolete autosomal recessive nail dysplasia
  Acute leukaemia
  Acute myelogenous leukaemia
  Adenoma
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Depression
  Endometrial cancer
  Endometrial carcinoma
  Esophageal squamous cell carcinoma
  Neural tube defect
  Non-immune hydrops fetalis
  Pituitary tumor
  Pneumocystis pneumonia
  Prostate cancer
  Prostate carcinoma
  Triple negative breast cancer
  Neoplasm
  Pancreatic cancer
  Small lymphocytic lymphoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Advanced cancer
  Gastric cancer
  Lateral meningocele syndrome
  Limb-mammary syndrome
  Metastatic malignant neoplasm
  Neuroblastoma
  Stomach cancer
• UniProt ID: FZD6_HUMAN
• Pfam ID: PF01534 ; PF01392
• Sequence:
  MEMFTFLLTCIFLPLLRGHSLFTCEPITVPRCMKMAYNMTFFPNLMGHYDQSIAAVEMEH
  FLPLANLECSPNIETFLCKAFVPTCIEQIHVVPPCRKLCEKVYSDCKKLIDTFGIRWPEE
  LECDRLQYCDETVPVTFDPHTEFLGPQKKTEQVQRDIGFWCPRHLKTSGGQGYKFLGIDQ
  CAPPCPNMYFKSDELEFAKSFIGTVSIFCLCATLFTFLTFLIDVRRFRYPERPIIYYSVC
  YSIVSLMYFIGFLLGDSTACNKADEKLELGDTVVLGSQNKACTVLFMLLYFFTMAGTVWW
  VILTITWFLAAGRKWSCEAIEQKAVWFHAVAWGTPGFLTVMLLAMNKVEGDNISGVCFVG
  LYDLDASRYFVLLPLCLCVFVGLSLLLAGIISLNHVRQVIQHDGRNQEKLKKFMIRIGVF
  SGLYLVPLVTLLGCYVYEQVNRITWEITWVSDHCRQYHIPCPYQAKAKARPELALFMIKY
  LMTLIVGISAVFWVGSKKTCTEWAGFFKRNRKRDPISESRRVLQESCEFFLKHNSKVKHK
  KKHYKPSSHKLKVISKSMGTSTGATANHGTSAVAITSHDYLGQETLTEIQTSPETSMREV
  KADGASTPRLREQDCGEPASPAASISRLSGEQVDGKGQAGSVSESARSEGRISPKSDITD
  TGLAQSNNLQVPSSSEPSSLKGSTSLLVHPVSGVRKEQGGGCHSDT
• Function: Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Together with FZD3, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear.
• Tissue Specificity: Detected in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, thymus, prostate, testis, ovary, small intestine and colon. In the fetus, expressed in brain, lung, liver and kidney.
• KEGG Pathway:
  mTOR sig.ling pathway (hsa04150)
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Melanogenesis (hsa04916)
  Cushing syndrome (hsa04934)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Basal cell carcinoma (hsa05217)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Ca2+ pathway (R-HSA-4086398)
  PCP/CE pathway (R-HSA-4086400)
  Regulation of FZD by ubiquitination (R-HSA-4641263)
  Signaling by RNF43 mutants (R-HSA-5340588)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Obsolete autosomal recessive nail dysplasia	DISOB289	Definitive	Autosomal recessive	[2]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Adenoma	DIS78ZEV	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[6]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Depression	DIS3XJ69	Strong	Biomarker	[8]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[9]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[10]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[11]
Non-immune hydrops fetalis	DISPUY8C	Strong	Genetic Variation	[12]
Pituitary tumor	DISN67JD	Strong	Altered Expression	[5]
Pneumocystis pneumonia	DISFSOM3	Strong	Altered Expression	[13]
Prostate cancer	DISF190Y	Strong	Altered Expression	[14]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[14]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	moderate	Biomarker	[14]
Pancreatic cancer	DISJC981	moderate	Biomarker	[15]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[16]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Disputed	Biomarker	[17]
Liver cancer	DISDE4BI	Disputed	Biomarker	[17]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Gastric cancer	DISXGOUK	Limited	Biomarker	[18]
Lateral meningocele syndrome	DISG74RP	Limited	Biomarker	[19]
Limb-mammary syndrome	DIS7H4FP	Limited	Biomarker	[19]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[19]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[20]
Stomach cancer	DISKIJSX	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Frizzled-6 (FZD6).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Frizzled-6 (FZD6).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Frizzled-6 (FZD6).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Frizzled-6 (FZD6).	[32]

14 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 Frizzled-6 (FZD6).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Frizzled-6 (FZD6).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Frizzled-6 (FZD6).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Frizzled-6 (FZD6).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Frizzled-6 (FZD6).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Frizzled-6 (FZD6).	[27]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Frizzled-6 (FZD6).	[27]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Frizzled-6 (FZD6).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Frizzled-6 (FZD6).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Frizzled-6 (FZD6).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Frizzled-6 (FZD6).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Frizzled-6 (FZD6).	[33]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Frizzled-6 (FZD6).	[34]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Frizzled-6 (FZD6).	[35]

References

• [1] A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways.Nat Commun. 2016 Oct 4;7:12885. doi: 10.1038/ncomms12885.
• [2] Mutations in Frizzled 6 cause isolated autosomal-recessive nail dysplasia. Am J Hum Genet. 2011 Jun 10;88(6):852-860. doi: 10.1016/j.ajhg.2011.05.013.
• [3] Biparental inheritance of chromosomal abnormalities in male twins with non-syndromic mental retardation.Eur J Med Genet. 2011 Jul-Aug;54(4):e383-8. doi: 10.1016/j.ejmg.2011.03.008. Epub 2011 Mar 21.
• [4] lncRNA PCAT-1 interacting with FZD6 contributes to the malignancy of acute myeloid leukemia cells through activating Wnt/-catenin signaling pathway.Am J Transl Res. 2019 Nov 15;11(11):7104-7114. eCollection 2019.
• [5] Expression of Wnt4 in human pituitary adenomas regulates activation of the beta-catenin-independent pathway.Endocr Pathol. 2008 Winter;19(4):261-73. doi: 10.1007/s12022-008-9048-9.
• [6] Functional and prognostic significance of the genomic amplification of frizzled 6 (FZD6) in breast cancer.J Pathol. 2017 Feb;241(3):350-361. doi: 10.1002/path.4841. Epub 2016 Dec 29.
• [7] NPTX2 promotes colorectal cancer growth and liver metastasis by the activation of the canonical Wnt/-catenin pathway via FZD6.Cell Death Dis. 2019 Mar 4;10(3):217. doi: 10.1038/s41419-019-1467-7.
• [8] Analysis of target genes regulated by chronic electroconvulsive therapy reveals role for Fzd6 in depression.Biol Psychiatry. 2012 Jan 1;71(1):51-8. doi: 10.1016/j.biopsych.2011.08.004. Epub 2011 Sep 19.
• [9] Targeting cancer stem cell signature gene SMOC-2 Overcomes chemoresistance and inhibits cell proliferation of endometrial carcinoma.EBioMedicine. 2019 Feb;40:276-289. doi: 10.1016/j.ebiom.2018.12.044. Epub 2018 Dec 26.
• [10] The prognostic role of FZD6 in esophageal squamous cell carcinoma patients.Clin Transl Oncol. 2020 Jul;22(7):1172-1179. doi: 10.1007/s12094-019-02243-3. Epub 2019 Nov 20.
• [11] Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population.Neurol Sci. 2014 Nov;35(11):1701-6. doi: 10.1007/s10072-014-1815-4. Epub 2014 May 10.
• [12] Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. Genome Biol. 2015 Jun 3;16(1):116. doi: 10.1186/s13059-015-0681-6.
• [13] Molecular cloning, characterization and expression analysis of Frizzled 6 in the small intestine of pigs (Sus scrofa).PLoS One. 2017 Jun 14;12(6):e0179421. doi: 10.1371/journal.pone.0179421. eCollection 2017.
• [14] Luteolin attenuates Wnt signaling via upregulation of FZD6 to suppress prostate cancer stemness revealed by comparative proteomics.Sci Rep. 2018 Jun 4;8(1):8537. doi: 10.1038/s41598-018-26761-2.
• [15] Long noncoding RNA DLX6-AS1 promotes tumorigenesis by modulating miR-497-5p/FZD4/FZD6/Wnt/-catenin pathway in pancreatic cancer.Cancer Manag Res. 2019 May 7;11:4209-4221. doi: 10.2147/CMAR.S194453. eCollection 2019.
• [16] Dysregulation of Frizzled 6 is a critical component of B-cell leukemogenesis in a mouse model of chronic lymphocytic leukemia.Blood. 2009 Mar 26;113(13):3031-9. doi: 10.1182/blood-2008-06-163303. Epub 2009 Jan 28.
• [17] LncFZD6 initiates Wnt/-catenin and liver TIC self-renewal through BRG1-mediated FZD6 transcriptional activation.Oncogene. 2018 Jun;37(23):3098-3112. doi: 10.1038/s41388-018-0203-6. Epub 2018 Mar 14.
• [18] WNT/PCP signaling pathway and human cancer (review).Oncol Rep. 2005 Dec;14(6):1583-8.
• [19] Uterine leiomyosarcoma and endometrial stromal sarcoma have unique miRNA signatures.Gynecol Oncol. 2016 Mar;140(3):512-7. doi: 10.1016/j.ygyno.2016.01.001. Epub 2016 Jan 6.
• [20] Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas.Oncotarget. 2011 Dec;2(12):976-83. doi: 10.18632/oncotarget.410.
• [21] 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.
• [22] 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.
• [23] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [24] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [25] 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.
• [26] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [27] 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.
• [28] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [29] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [30] 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.
• [31] BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells. Stem Cell Res Ther. 2016 Feb 1;7:22. doi: 10.1186/s13287-016-0278-3.
• [32] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [33] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [34] 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.
• [35] Lithium chloride regulates the proliferation of stem-like cells in retinoblastoma cell lines: a potential role for the canonical Wnt signaling pathway. Mol Vis. 2010 Jan 13;16:36-45.