Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOGZ85M)

• DOT Name: C-C motif chemokine 15 (CCL15)
• Synonyms: Chemokine CC-2; HCC-2; Leukotactin-1; LKN-1; MIP-1 delta; Macrophage inflammatory protein 5; MIP-5; Mrp-2b; NCC-3; Small-inducible cytokine A15
• Gene Name: CCL15
• Related Disease:
  Advanced cancer
  Carcinoma of esophagus
  Chronic renal failure
  Colorectal carcinoma
  Diabetic retinopathy
  Epithelial ovarian cancer
  Esophageal cancer
  Hepatocellular carcinoma
  Hypersensitivity pneumonitis
  Inflammatory bowel disease
  Metastatic malignant neoplasm
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Sarcoidosis
  X-linked reticulate pigmentary disorder
  Head-neck squamous cell carcinoma
  Thyroid gland follicular carcinoma
  Multiple sclerosis
  Asthma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: CCL15_HUMAN
• PDB ID: 2HCC; 7VL9; 7VLA
• Pfam ID: PF00048
• Sequence:
  MKVSVAALSCLMLVAVLGSQAQFTNDAETELMMSKLPLENPVVLNSFHFAADCCTSYISQ
  SIPCSLMKSYFETSSECSKPGVIFLTKKGRQVCAKPSGPGVQDCMKKLKPYSI
• Function: Chemotactic factor that attracts T-cells and monocytes, but not neutrophils, eosinophils, or B-cells. Acts mainly via CC chemokine receptor CCR1. Also binds to CCR3. CCL15(22-92), CCL15(25-92) and CCL15(29-92) are more potent chemoattractants than the CCL15.
• Tissue Specificity: Most abundant in heart, skeletal muscle and adrenal gland. Lower levels in placenta, liver, pancreas and bone marrow. CCL15(22-92), CCL15(25-92) and CCL15(29-92) are found in high levels in synovial fluids from rheumatoid patients.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[2]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Hypersensitivity pneumonitis	DIS5IW5K	Strong	Altered Expression	[8]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[1]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[10]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Altered Expression	[5]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[11]
Thyroid gland follicular carcinoma	DISFK2QT	moderate	Biomarker	[12]
Multiple sclerosis	DISB2WZI	Disputed	Genetic Variation	[13]
Asthma	DISW9QNS	Limited	Biomarker	[14]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[15]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[15]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[15]

2 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 C-C motif chemokine 15 (CCL15).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-C motif chemokine 15 (CCL15).	[22]

7 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 C-C motif chemokine 15 (CCL15).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of C-C motif chemokine 15 (CCL15).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of C-C motif chemokine 15 (CCL15).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of C-C motif chemokine 15 (CCL15).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of C-C motif chemokine 15 (CCL15).	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of C-C motif chemokine 15 (CCL15).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of C-C motif chemokine 15 (CCL15).	[23]

References

• [1] Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis.Clin Cancer Res. 2017 Feb 1;23(3):833-844. doi: 10.1158/1078-0432.CCR-16-0520. Epub 2016 Aug 4.
• [2] Circulating Inflammation Markers and Risk of Gastric and Esophageal Cancers: A Case-Cohort Study Within the Japan Public Health Center-Based Prospective Study.Cancer Epidemiol Biomarkers Prev. 2019 Apr;28(4):829-832. doi: 10.1158/1055-9965.EPI-18-1157. Epub 2019 Mar 15.
• [3] Increase of expression and activation of chemokine CCL15 in chronic renal failure.Biochem Biophys Res Commun. 2006 Jul 14;345(4):1504-12. doi: 10.1016/j.bbrc.2006.05.057. Epub 2006 May 17.
• [4] TRIM47 is up-regulated in colorectal cancer, promoting ubiquitination and degradation of SMAD4.J Exp Clin Cancer Res. 2019 Apr 12;38(1):159. doi: 10.1186/s13046-019-1143-x.
• [5] Comprehensive analysis of vitreous humor chemokines in type 2 diabetic patients with and without diabetic retinopathy.Acta Diabetol. 2019 Jul;56(7):797-805. doi: 10.1007/s00592-019-01317-6. Epub 2019 Mar 25.
• [6] Chemokine Network and Overall Survival in TP53 Wild-Type and Mutant Ovarian Cancer.Immune Netw. 2018 Aug 13;18(4):e29. doi: 10.4110/in.2018.18.e29. eCollection 2018 Aug.
• [7] CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma.Hepatology. 2019 Jan;69(1):143-159. doi: 10.1002/hep.30134. Epub 2018 Dec 31.
• [8] C-C Motif Chemokine Ligand 15 May Be a Useful Biomarker for Predicting the Prognosis of Patients with Chronic Hypersensitivity Pneumonitis.Respiration. 2019;98(3):212-220. doi: 10.1159/000500576. Epub 2019 Aug 15.
• [9] A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa.Mucosal Immunol. 2010 Jan;3(1):40-8. doi: 10.1038/mi.2009.115. Epub 2009 Oct 7.
• [10] Expression of macrophage inflammatory protein-3 beta/CCL19 in pulmonary sarcoidosis.Am J Respir Crit Care Med. 2003 Jun 15;167(12):1695-703. doi: 10.1164/rccm.200205-487OC. Epub 2003 Mar 5.
• [11] Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells.Cell Oncol (Dordr). 2019 Aug;42(4):459-475. doi: 10.1007/s13402-019-00446-y. Epub 2019 Apr 17.
• [12] Follicular thyroid carcinoma but not adenoma recruits tumor-associated macrophages by releasing CCL15.BMC Cancer. 2016 Feb 15;16:98. doi: 10.1186/s12885-016-2114-7.
• [13] Haplotypes within genes of beta-chemokines in 17q11 are associated with multiple sclerosis: a second phase study.Hum Genet. 2005 Oct;118(1):67-75. doi: 10.1007/s00439-005-0003-2. Epub 2005 Aug 3.
• [14] CC-chemokine CCL15 expression and possible implications for the pathogenesis of IgE-related severe asthma.Mediators Inflamm. 2012;2012:475253. doi: 10.1155/2012/475253. Epub 2012 Oct 31.
• [15] Role of Chemokines in Thyroid Cancer Microenvironment: Is CXCL8 the Main Player?.Front Endocrinol (Lausanne). 2018 Jun 21;9:314. doi: 10.3389/fendo.2018.00314. eCollection 2018.
• [16] 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.
• [17] 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.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] 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.
• [20] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [21] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [22] 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.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.