Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLWJ8CJ)

• DOT Name: C-C motif chemokine 25 (CCL25)
• Synonyms: Chemokine TECK; Small-inducible cytokine A25; Thymus-expressed chemokine
• Gene Name: CCL25
• Related Disease:
  T-cell acute lymphoblastic leukaemia
  Allergic asthma
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chronic eosinophilic leukemia
  Craniosynostosis
  Cutaneous melanoma
  Epithelial ovarian cancer
  Lung cancer
  Lung carcinoma
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Peeling skin syndrome 1
  Potocki-Shaffer syndrome
  Primary sclerosing cholangitis
  Prostate cancer
  Prostate carcinoma
  Retinal vein occlusion
  Rheumatoid arthritis
  Sjogren syndrome
  Systemic sclerosis
  Ulcerative colitis
  Nasopharyngeal carcinoma
  Stroke
  Crohn disease
  Endometriosis
  Inflammatory bowel disease
  Nervous system inflammation
  Ovarian neoplasm
  Periodontitis
  Serous cystadenocarcinoma
• UniProt ID: CCL25_HUMAN
• Pfam ID: PF00048
• Sequence:
  MNLWLLACLVAGFLGAWAPAVHTQGVFEDCCLAYHYPIGWAVLRRAWTYRIQEVSGSCNL
  PAAIFYLPKRHRKVCGNPKSREVQRAMKLLDARNKVFAKLHHNTQTFQAGPHAVKKLSSG
  NSKLSSSKFSNPISSSKRNVSLLISANSGL
• Function: Potentially involved in T-cell development. Recombinant protein shows chemotactic activity on thymocytes, macrophages, THP-1 cells, and dendritics cells but is inactive on peripheral blood lymphocytes and neutrophils. Binds to CCR9. Isoform 2 is an antagonist of isoform 1. Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4.
• Tissue Specificity: Specifically expressed by thymic dendritic cells. High levels in thymus and small intestine.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
  Intesti.l immune network for IgA production (hsa04672)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[1]
Allergic asthma	DISHF0H3	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Chronic eosinophilic leukemia	DISAJOUO	Strong	Biomarker	[6]
Craniosynostosis	DIS6J405	Strong	Altered Expression	[7]
Cutaneous melanoma	DIS3MMH9	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Melanoma	DIS1RRCY	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Peeling skin syndrome 1	DIS35574	Strong	Biomarker	[11]
Potocki-Shaffer syndrome	DISKGU59	Strong	Biomarker	[11]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Altered Expression	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Retinal vein occlusion	DISSVWOE	Strong	Altered Expression	[14]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[15]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[11]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[11]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[16]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[17]
Stroke	DISX6UHX	moderate	Altered Expression	[18]
Crohn disease	DIS2C5Q8	Limited	Altered Expression	[19]
Endometriosis	DISX1AG8	Limited	Biomarker	[20]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[21]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[22]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[9]
Periodontitis	DISI9JOI	Limited	Biomarker	[23]
Serous cystadenocarcinoma	DISVK716	Limited	Altered Expression	[9]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the secretion of C-C motif chemokine 25 (CCL25).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of C-C motif chemokine 25 (CCL25).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of C-C motif chemokine 25 (CCL25).	[26]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of C-C motif chemokine 25 (CCL25).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of C-C motif chemokine 25 (CCL25).	[27]

References

• [1] NHE1 has a notable role in metastasis and drug resistance of T-cell acute lymphoblastic leukemia.Oncol Lett. 2017 Oct;14(4):4256-4262. doi: 10.3892/ol.2017.6716. Epub 2017 Aug 3.
• [2] V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ T cells upon CD226 engagement.J Immunol. 2005 Oct 15;175(8):4914-26. doi: 10.4049/jimmunol.175.8.4914.
• [3] Angiotensin-converting enzyme inhibition down-regulates the pro-atherogenic chemokine receptor 9 (CCR9)-chemokine ligand 25 (CCL25) axis.J Biol Chem. 2010 Jul 23;285(30):23496-505. doi: 10.1074/jbc.M110.117481. Epub 2010 May 26.
• [4] 4T1 Mammary Carcinoma Colonization of Metastatic Niches Is Accelerated by Obesity.Front Oncol. 2019 Sep 20;9:685. doi: 10.3389/fonc.2019.00685. eCollection 2019.
• [5] CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion.Int J Oncol. 2011 May;38(5):1279-85. doi: 10.3892/ijo.2011.953. Epub 2011 Feb 23.
• [6] Human eosinophils show chemotaxis to lymphoid chemokines and exhibit antigen-presenting-cell-like properties upon stimulation with IFN-gamma, IL-3 and GM-CSF.Int Arch Allergy Immunol. 2008;146(3):227-34. doi: 10.1159/000115891. Epub 2008 Feb 11.
• [7] Increased Expressions and Roles of CC Chemokine Ligand 21 and CC Chemokine Ligand 25 in Chronic Rhinosinusitis with Nasal Polyps.Int Arch Allergy Immunol. 2020;181(3):159-169. doi: 10.1159/000504476. Epub 2019 Dec 11.
• [8] Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine.Clin Cancer Res. 2008 Feb 1;14(3):638-45. doi: 10.1158/1078-0432.CCR-07-2025.
• [9] Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer.Int J Oncol. 2011 Aug;39(2):373-81. doi: 10.3892/ijo.2011.1059. Epub 2011 May 31.
• [10] CCR9-CCL25 interaction suppresses apoptosis of lung cancer cells by activating the PI3K/Akt pathway.Med Oncol. 2015 Mar;32(3):66. doi: 10.1007/s12032-015-0531-0. Epub 2015 Feb 18.
• [11] Decreased circulating CXCR3+CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjgren's syndrome to facilitate their concerted migration.Scand J Immunol. 2020 Mar;91(3):e12852. doi: 10.1111/sji.12852. Epub 2019 Dec 13.
• [12] Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity.J Autoimmun. 2016 Apr;68:98-104. doi: 10.1016/j.jaut.2016.01.001. Epub 2016 Feb 9.
• [13] Expression and functional role of CCR9 in prostate cancer cell migration and invasion.Clin Cancer Res. 2004 Dec 15;10(24):8743-50. doi: 10.1158/1078-0432.CCR-04-0266.
• [14] Comprehensive analysis of vitreous chemokines involved in ischemic retinal vein occlusion.Mol Vis. 2019 Nov 15;25:756-765. eCollection 2019.
• [15] Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice.Arthritis Res Ther. 2014 Sep 24;16(5):445. doi: 10.1186/s13075-014-0445-9.
• [16] Randomised, Double-blind, Placebo-controlled Trial of CCR9-targeted Leukapheresis Treatment of Ulcerative Colitis Patients.J Crohns Colitis. 2017 May 1;11(5):534-542. doi: 10.1093/ecco-jcc/jjw196.
• [17] Intracellular expression profile and clinical significance of the CCR9-CCL25 chemokine receptor complex in nasopharyngeal carcinoma.J Laryngol Otol. 2015 Oct;129(10):1013-9. doi: 10.1017/S0022215115002108. Epub 2015 Aug 17.
• [18] Ischemic stroke damages the intestinal mucosa and induces alteration of the intestinal lymphocytes and CCL19 mRNA in rats.Neurosci Lett. 2017 Sep 29;658:165-170. doi: 10.1016/j.neulet.2017.08.061. Epub 2017 Aug 30.
• [19] CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn's disease.Gastroenterology. 2001 Aug;121(2):246-54. doi: 10.1053/gast.2001.27154.
• [20] CD33(+) CD14(+) CD11b(+) HLA-DR(-) monocytic myeloid-derived suppressor cells recruited and activated by CCR9/CCL25 are crucial for the pathogenic progression of endometriosis.Am J Reprod Immunol. 2019 Jan;81(1):e13067. doi: 10.1111/aji.13067. Epub 2018 Nov 16.
• [21] Chemokines and Chemokine Receptors as Therapeutic Targets in Inflammatory Bowel Disease; Pitfalls and Promise.J Crohns Colitis. 2018 Aug 22;12(suppl_2):S641-S652. doi: 10.1093/ecco-jcc/jjx145.
• [22] Toll-Like Receptor 4 Promotes Th17 Lymphocyte Infiltration Via CCL25/CCR9 in Pathogenesis of Experimental Autoimmune Encephalomyelitis.J Neuroimmune Pharmacol. 2019 Sep;14(3):493-502. doi: 10.1007/s11481-019-09854-1. Epub 2019 May 8.
• [23] Epigenetic characteristics in inflammatory candidate genes in aggressive periodontitis.Hum Immunol. 2016 Jan;77(1):71-75. doi: 10.1016/j.humimm.2015.10.007. Epub 2015 Oct 21.
• [24] Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol. 2021 Feb;95(2):727-747. doi: 10.1007/s00204-020-02946-5. Epub 2021 Jan 25.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [27] 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.
• [28] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.