Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW9X7BQ)

• DOT Name: Neuromedin-U (NMU)
• Gene Name: NMU
• Related Disease:
  Advanced cancer
  Bladder cancer
  Breast neoplasm
  Colorectal carcinoma
  Coronary atherosclerosis
  Dilated cardiomyopathy
  Endometrial carcinoma
  HER2/NEU overexpressing breast cancer
  Kidney cancer
  Kidney neoplasm
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Myocardial ischemia
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Non-small-cell lung cancer
  Pituitary gland disorder
  Pneumonia
  Pneumonitis
  Renal carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Breast carcinoma
  Matthew-Wood syndrome
  Obesity
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Bone osteosarcoma
  Osteosarcoma
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Breast disorder
  Head-neck squamous cell carcinoma
  Metastatic malignant neoplasm
  Myeloid leukaemia
• UniProt ID: NMU_HUMAN
• PDB ID: 7W53; 7W55; 7XK8
• Pfam ID: PF02070
• Sequence:
  MLRTESCRPRSPAGQVAAASPLLLLLLLLAWCAGACRGAPILPQGLQPEQQLQLWNEIDD
  TCSSFLSIDSQPQASNALEELCFMIMGMLPKPQEQDEKDNTKRFLFHYSKTQKLGKSNVV
  SSVVHPLLQLVPHLHERRMKRFRVDEEFQSPFASQSRGYFLFRPRNGRRSAGFI
• Function: [Neuromedin-U-25]: Ligand for receptors NMUR1 and NMUR2. Stimulates muscle contractions of specific regions of the gastrointestinal tract. In humans, NmU stimulates contractions of the ileum and urinary bladder; [Neuromedin precursor-related peptide 33]: Does not function as a ligand for either NMUR1 or NMUR2. Indirectly induces prolactin release although its potency is much lower than that of neuromedin precursor-related peptide 36; [Neuromedin precursor-related peptide 36]: Does not function as a ligand for either NMUR1 or NMUR2. Indirectly induces prolactin release from lactotroph cells in the pituitary gland, probably via the hypothalamic dopaminergic system.
• Tissue Specificity: Expressed throughout the enteric nervous system with highest levels being found in the jejunum.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (i) signalling events (R-HSA-418594)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[5]
Dilated cardiomyopathy	DISX608J	Strong	Altered Expression	[5]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[6]
HER2/NEU overexpressing breast cancer	DISYKID5	Strong	Altered Expression	[7]
Kidney cancer	DISBIPKM	Strong	Biomarker	[8]
Kidney neoplasm	DISBNZTN	Strong	Altered Expression	[8]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[10]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[12]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Pituitary gland disorder	DIS7XB48	Strong	Biomarker	[14]
Pneumonia	DIS8EF3M	Strong	Biomarker	[15]
Pneumonitis	DIS88E0K	Strong	Biomarker	[15]
Renal carcinoma	DISER9XT	Strong	Biomarker	[8]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	moderate	Biomarker	[3]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[3]
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[16]
Obesity	DIS47Y1K	moderate	Biomarker	[17]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[16]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[16]
Bone osteosarcoma	DIST1004	Disputed	Biomarker	[18]
Osteosarcoma	DISLQ7E2	Disputed	Biomarker	[18]
Acute lymphocytic leukaemia	DISPX75S	Limited	Altered Expression	[19]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[19]
Breast disorder	DISJTGMA	Limited	Biomarker	[20]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[21]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[22]
Myeloid leukaemia	DISMN944	Limited	Altered Expression	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Neuromedin-U (NMU) affects the response to substance of Cisplatin.	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Neuromedin-U (NMU).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Neuromedin-U (NMU).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neuromedin-U (NMU).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Neuromedin-U (NMU).	[26]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neuromedin-U (NMU).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Neuromedin-U (NMU).	[28]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Neuromedin-U (NMU).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Neuromedin-U (NMU).	[30]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Neuromedin-U (NMU).	[29]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Neuromedin-U (NMU).	[31]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Neuromedin-U (NMU).	[32]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Neuromedin-U (NMU).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuromedin-U (NMU).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Neuromedin-U (NMU).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuromedin-U (NMU).	[36]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Neuromedin-U (NMU).	[37]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Neuromedin-U (NMU).	[27]

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 Neuromedin-U (NMU).	[35]

References

• [1] Neuromedin U: A Small Peptide in the Big World of Cancer.Cancers (Basel). 2019 Sep 5;11(9):1312. doi: 10.3390/cancers11091312.
• [2] Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia.Oncogene. 2007 Feb 1;26(5):765-73. doi: 10.1038/sj.onc.1209835. Epub 2006 Jul 31.
• [3] Oncogenic features of neuromedin U in breast cancer are associated with NMUR2 expression involving crosstalk with members of the WNT signaling pathway.Oncotarget. 2017 May 30;8(22):36246-36265. doi: 10.18632/oncotarget.16121.
• [4] The Long Noncoding RNA, LINC01555, Promotes Invasion and Metastasis of Colorectal Cancer by Activating the Neuropeptide, Neuromedin U.Med Sci Monit. 2019 May 30;25:4014-4024. doi: 10.12659/MSM.916508.
• [5] Expression and vasoconstrictor function of anorexigenic peptides neuromedin U-25 and S in the human cardiovascular system.Cardiovasc Res. 2009 Feb 1;81(2):353-61. doi: 10.1093/cvr/cvn302. Epub 2008 Nov 5.
• [6] Long non-coding RNA HAND2-AS1 inhibits invasion and metastasis in endometrioid endometrial carcinoma through inactivating neuromedin U.Cancer Lett. 2018 Jan 28;413:23-34. doi: 10.1016/j.canlet.2017.10.028. Epub 2017 Oct 26.
• [7] Neuromedin U alters bioenergetics and expands the cancer stem cell phenotype in HER2-positive breast cancer.Int J Cancer. 2017 Jun 15;140(12):2771-2784. doi: 10.1002/ijc.30705.
• [8] Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells.Mol Cancer. 2011 Jul 26;10:89. doi: 10.1186/1476-4598-10-89.
• [9] Secreted phosphoprotein 1 upstream invasive network construction and analysis of lung adenocarcinoma compared with human normal adjacent tissues by integrative biocomputation.Cell Biochem Biophys. 2010 Apr;56(2-3):59-71. doi: 10.1007/s12013-009-9071-6.
• [10] The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer.Cancer Res. 2006 Oct 1;66(19):9408-19. doi: 10.1158/0008-5472.CAN-06-1349.
• [11] Effects of the pesticide chlorpyrifos on breast cancer disease. Implication of epigenetic mechanisms.J Steroid Biochem Mol Biol. 2019 Feb;186:96-104. doi: 10.1016/j.jsbmb.2018.09.021. Epub 2018 Oct 2.
• [12] Role of neuromedin U in accelerating of non-alcoholic steatohepatitis in mice.Peptides. 2018 Jan;99:134-141. doi: 10.1016/j.peptides.2017.09.011. Epub 2017 Oct 7.
• [13] Identification of NMU as a potential gene conferring alectinib resistance in non-small cell lung cancer based on bioinformatics analyses.Gene. 2018 Dec 15;678:137-142. doi: 10.1016/j.gene.2018.08.032. Epub 2018 Aug 7.
• [14] A PEGylated analog of short-length Neuromedin U with potent anorectic and anti-obesity effects.Bioorg Med Chem. 2017 Apr 15;25(8):2307-2312. doi: 10.1016/j.bmc.2017.02.023. Epub 2017 Feb 21.
• [15] The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation.Nature. 2017 Sep 21;549(7672):351-356. doi: 10.1038/nature24029. Epub 2017 Sep 13.
• [16] Neuromedin U is overexpressed in pancreatic cancer and increases invasiveness via the hepatocyte growth factor c-Met pathway.Cancer Lett. 2009 May 8;277(1):72-81. doi: 10.1016/j.canlet.2008.11.028. Epub 2008 Dec 31.
• [17] PEGylated neuromedin U-8 shows long-lasting anorectic activity and anti-obesity effect in mice by peripheral administration.Peptides. 2017 Aug;94:99-105. doi: 10.1016/j.peptides.2017.04.001. Epub 2017 Apr 8.
• [18] Abnormal DNA methylation may contribute to the progression of osteosarcoma.Mol Med Rep. 2018 Jan;17(1):193-199. doi: 10.3892/mmr.2017.7869. Epub 2017 Oct 25.
• [19] Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid leukemias.Blood. 2004 Sep 15;104(6):1833-40. doi: 10.1182/blood-2003-10-3577. Epub 2004 Jun 8.
• [20] Gene expression profiling of NMU-induced rat mammary tumors: cross species comparison with human breast cancer.Carcinogenesis. 2005 Aug;26(8):1343-53. doi: 10.1093/carcin/bgi100. Epub 2005 Apr 21.
• [21] Overexpression of neuromedin U is correlated with regional metastasis of head and neck squamous cell carcinoma.Mol Med Rep. 2016 Aug;14(2):1075-82. doi: 10.3892/mmr.2016.5347. Epub 2016 May 27.
• [22] The YAP1-NMU Axis Is Associated with Pancreatic Cancer Progression and Poor Outcome: Identification of a Novel Diagnostic Biomarker and Therapeutic Target.Cancers (Basel). 2019 Sep 30;11(10):1477. doi: 10.3390/cancers11101477.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] 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.
• [25] 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.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [28] 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.
• [29] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [30] 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.
• [31] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [32] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [33] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [34] Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J Surg Res. 2007 Apr;138(2):163-9. doi: 10.1016/j.jss.2006.05.037. Epub 2007 Jan 25.
• [35] 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.
• [36] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [38] 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.