Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOOQI1F)

• DOT Name: C-C motif chemokine 16 (CCL16)
• Synonyms: Chemokine CC-4; HCC-4; Chemokine LEC; IL-10-inducible chemokine; LCC-1; Liver-expressed chemokine; Lymphocyte and monocyte chemoattractant; LMC; Monotactin-1; MTN-1; NCC-4; Small-inducible cytokine A16
• Gene Name: CCL16
• Related Disease:
  Cataract
  OPTN-related open angle glaucoma
  Type-1/2 diabetes
  Cervical cancer
  Cervical carcinoma
  Endometriosis
  Eosinophilic pneumonia
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Irritable bowel syndrome
  Melanoma
  Non-insulin dependent diabetes
  Post-traumatic stress disorder
  Prostate neoplasm
  Sarcoidosis
  Breast cancer
  Breast carcinoma
  Neoplasm
• UniProt ID: CCL16_HUMAN
• PDB ID: 5LTL; 7SCT
• Pfam ID: PF00048
• Sequence:
  MKVSEAALSLLVLILIITSASRSQPKVPEWVNTPSTCCLKYYEKVLPRRLVVGYRKALNC
  HLPAIIFVTKRNREVCTNPNDDWVQEYIKDPNLPLLPTRNLSTVKIITAKNGQPQLLNSQ
• Function: Shows chemotactic activity for lymphocytes and monocytes but not neutrophils. Also shows potent myelosuppressive activity, suppresses proliferation of myeloid progenitor cells. Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1 monocytes, but not for resting lymphocytes and neutrophils. Induces a calcium flux in THP-1 cells that were desensitized by prior expression to RANTES.
• Tissue Specificity: Mainly expressed in liver, also found in spleen and thymus. Highly expressed in LPS- and IFN-gamma-activated monocytes, weakly in some lymphocytes, including natural killer cells, gamma-delta T-cells, and some T-cell clones.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract	DISUD7SL	Definitive	Biomarker	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Genetic Variation	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Endometriosis	DISX1AG8	Strong	Altered Expression	[4]
Eosinophilic pneumonia	DISTRF6P	Strong	Altered Expression	[5]
Hepatitis	DISXXX35	Strong	Biomarker	[6]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Irritable bowel syndrome	DIS27206	Strong	Altered Expression	[7]
Melanoma	DIS1RRCY	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]
Post-traumatic stress disorder	DISHL1EY	Strong	Genetic Variation	[9]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[10]
Sarcoidosis	DISE5B8Z	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Disputed	Biomarker	[11]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[11]
Neoplasm	DISZKGEW	Disputed	Genetic Variation	[11]

7 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 C-C motif chemokine 16 (CCL16).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of C-C motif chemokine 16 (CCL16).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of C-C motif chemokine 16 (CCL16).	[14]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of C-C motif chemokine 16 (CCL16).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of C-C motif chemokine 16 (CCL16).	[16]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of C-C motif chemokine 16 (CCL16).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of C-C motif chemokine 16 (CCL16).	[17]

References

• [1] Age-related aqueous humor (AH) and lens epithelial cell/capsule protein carbonylation and AH protein concentration in cataract patients who have pseudoexfoliative diseases.Mol Vis. 2018 Dec 31;24:890-901. eCollection 2018.
• [2] Patient Reported Outcomes following initiation of Glucagon-like peptide-1 Receptor agonists in patients with type 2 Diabetes in a specialist endocrinology practice of the LMC diabetes registry: The PROGRESS-Diabetes study.Diabetes Res Clin Pract. 2019 Oct;156:107820. doi: 10.1016/j.diabres.2019.107820. Epub 2019 Aug 22.
• [3] Tumor-associated macrophages induce lymphangiogenesis in cervical cancer via interaction with tumor cells.APMIS. 2014 Nov;122(11):1059-69. doi: 10.1111/apm.12257. Epub 2014 Apr 4.
• [4] Laser capture microdissection and cDNA array analysis of endometrium identify CCL16 and CCL21 as epithelial-derived inflammatory mediators associated with endometriosis.Reprod Biol Endocrinol. 2007 May 17;5:18. doi: 10.1186/1477-7827-5-18.
• [5] Elevated concentrations of liver-expressed chemokine/CC chemokine ligand 16 in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia.Int Arch Allergy Immunol. 2009;150(3):282-90. doi: 10.1159/000222681. Epub 2009 Jun 4.
• [6] The alpha1-6-fucosyltransferase gene and its biological significance.Biochim Biophys Acta. 1999 Dec 6;1473(1):9-20. doi: 10.1016/s0304-4165(99)00166-x.
• [7] Pro-inflammatory chemokine C-C motif ligand 16 (CCL-16) dysregulation in irritable bowel syndrome (IBS): a pilot study.Neurogastroenterol Motil. 2011 Dec;23(12):1092-7. doi: 10.1111/j.1365-2982.2011.01792.x. Epub 2011 Sep 23.
• [8] Laminin-421 produced by lymphatic endothelial cells induces chemotaxis for human melanoma cells.Pigment Cell Melanoma Res. 2009 Oct;22(5):601-10. doi: 10.1111/j.1755-148X.2009.00590.x. Epub 2009 Jun 5.
• [9] Trauma-informed care improves management of paradoxical vocal fold movement patients.Laryngoscope. 2020 Jun;130(6):1508-1513. doi: 10.1002/lary.28279. Epub 2019 Sep 11.
• [10] Ultrasound-guided intra-tumor injection of combined immunotherapy cures mice from orthotopic prostate cancer.Cancer Immunol Immunother. 2013 Dec;62(12):1811-9. doi: 10.1007/s00262-013-1486-7. Epub 2013 Oct 18.
• [11] Risk of leptomeningeal carcinomatosis in patients with brain metastases treated with stereotactic radiosurgery.J Neurooncol. 2018 Jan;136(2):395-401. doi: 10.1007/s11060-017-2666-7. Epub 2017 Nov 20.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [16] 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.
• [17] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.