Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHQZXM1)

• DOT Name: Matrix metalloproteinase-28 (MMP28)
• Synonyms: MMP-28; EC 3.4.24.-; Epilysin
• Gene Name: MMP28
• Related Disease:
  Multiple sclerosis
  Adult glioblastoma
  Atrial fibrillation
  Autoimmune disease
  Carcinoma
  Cardiac failure
  Chondrosarcoma
  Chronic obstructive pulmonary disease
  Colitis
  Congestive heart failure
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hypersensitivity pneumonitis
  Lung carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Osteoarthritis
  Plasma cell myeloma
  Pneumonia
  Pneumonitis
  Pulmonary emphysema
  Pulmonary fibrosis
  Ulcerative colitis
  Gastric cancer
  Stomach cancer
  Amyotrophic lateral sclerosis
  Inflammatory bowel disease
• UniProt ID: MMP28_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF00045 ; PF00413 ; PF01471
• Sequence:
  MVARVGLLLRALQLLLWGHLDAQPAERGGQELRKEAEAFLEKYGYLNEQVPKAPTSTRFS
  DAIRAFQWVSQLPVSGVLDRATLRQMTRPRCGVTDTNSYAAWAERISDLFARHRTKMRRK
  KRFAKQGNKWYKQHLSYRLVNWPEHLPEPAVRGAVRAAFQLWSNVSALEFWEAPATGPAD
  IRLTFFQGDHNDGLGNAFDGPGGALAHAFLPRRGEAHFDQDERWSLSRRRGRNLFVVLAH
  EIGHTLGLTHSPAPRALMAPYYKRLGRDALLSWDDVLAVQSLYGKPLGGSVAVQLPGKLF
  TDFETWDSYSPQGRRPETQGPKYCHSSFDAITVDRQQQLYIFKGSHFWEVAADGNVSEPR
  PLQERWVGLPPNIEAAAVSLNDGDFYFFKGGRCWRFRGPKPVWGLPQLCRAGGLPRHPDA
  ALFFPPLRRLILFKGARYYVLARGGLQVEPYYPRSLQDWGGIPEEVSGALPRPDGSIIFF
  RDDRYWRLDQAKLQATTSGRWATELPWMGCWHANSGSALF
• Function: Can degrade casein. Could play a role in tissues homeostasis and repair.
• Tissue Specificity: Expressed at high levels in testes and lung. Low levels are detected in kidney, pancreas and skin. Also expressed in fetal lung, brain, skeletal muscle and kidney. Expressed selectively in keratinocytes. Widely expressed in several carcinomas as well. Is up-regulated in response to injury in the skin.

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Cardiac failure	DISDC067	Strong	Altered Expression	[3]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[7]
Colitis	DISAF7DD	Strong	Altered Expression	[8]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Hypersensitivity pneumonitis	DIS5IW5K	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[13]
Pneumonia	DIS8EF3M	Strong	Biomarker	[7]
Pneumonitis	DIS88E0K	Strong	Biomarker	[7]
Pulmonary emphysema	DIS5M7HZ	Strong	Biomarker	[14]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[4]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[8]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[15]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[15]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[16]
Inflammatory bowel disease	DISGN23E	Limited	Altered Expression	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Matrix metalloproteinase-28 (MMP28).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Matrix metalloproteinase-28 (MMP28).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Matrix metalloproteinase-28 (MMP28).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Matrix metalloproteinase-28 (MMP28).	[22]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Matrix metalloproteinase-28 (MMP28).	[23]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Matrix metalloproteinase-28 (MMP28).	[24]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Matrix metalloproteinase-28 (MMP28).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Matrix metalloproteinase-28 (MMP28).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Matrix metalloproteinase-28 (MMP28).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Matrix metalloproteinase-28 (MMP28).	[21]

References

• [1] Inflammatory proprotein convertase-matrix metalloproteinase proteolytic pathway in antigen-presenting cells as a step to autoimmune multiple sclerosis.J Biol Chem. 2009 Oct 30;284(44):30615-26. doi: 10.1074/jbc.M109.041244. Epub 2009 Sep 2.
• [2] Matrix metalloproteinase-19 is highly expressed in astroglial tumors and promotes invasion of glioma cells.J Neuropathol Exp Neurol. 2010 Mar;69(3):215-23. doi: 10.1097/NEN.0b013e3181ce9f67.
• [3] Potential roles of circulating matrix metalloproteinase-28 (MMP-28) in patients with atrial fibrillation.Life Sci. 2018 Jul 1;204:15-19. doi: 10.1016/j.lfs.2018.04.053. Epub 2018 May 2.
• [4] Identification of MMP28 as a biomarker for the differential diagnosis of idiopathic pulmonary fibrosis.PLoS One. 2018 Sep 12;13(9):e0203779. doi: 10.1371/journal.pone.0203779. eCollection 2018.
• [5] MMP-28, a new human matrix metalloproteinase with an unusual cysteine-switch sequence is widely expressed in tumors.Gene. 2001 Mar 7;265(1-2):87-93. doi: 10.1016/s0378-1119(01)00360-2.
• [6] Expression and function of matrix metalloproteinase (MMP)-28.Matrix Biol. 2009 Jun;28(5):263-72. doi: 10.1016/j.matbio.2009.04.006. Epub 2009 Apr 16.
• [7] Matrix Metalloproteinase-28 Is a Key Contributor to Emphysema Pathogenesis.Am J Pathol. 2017 Jun;187(6):1288-1300. doi: 10.1016/j.ajpath.2017.02.008. Epub 2017 Apr 8.
• [8] Cellular sources of MMP-7, MMP-13 and MMP-28 in ulcerative colitis.Scand J Gastroenterol. 2010 Oct;45(10):1186-96. doi: 10.3109/00365521.2010.499961.
• [9] The function of MMP-28/TGF- induced cell apoptosis in human glioma cells.Exp Ther Med. 2018 Oct;16(4):2867-2874. doi: 10.3892/etm.2018.6566. Epub 2018 Aug 2.
• [10] Upregulated MMP28 in Hepatocellular Carcinoma Promotes Metastasis via Notch3 Signaling and Predicts Unfavorable Prognosis.Int J Biol Sci. 2019 Feb 19;15(4):812-825. doi: 10.7150/ijbs.31335. eCollection 2019.
• [11] Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells.J Cell Sci. 2006 Sep 15;119(Pt 18):3856-65. doi: 10.1242/jcs.03157. Epub 2006 Aug 29.
• [12] MMP28 (epilysin) as a novel promoter of invasion and metastasis in gastric cancer.BMC Cancer. 2011 May 26;11:200. doi: 10.1186/1471-2407-11-200.
• [13] Human beta-defensin-1 and -2 and matrix metalloproteinase-25 and -26 expression in chronic and aggressive periodontitis and in peri-implantitis.Arch Oral Biol. 2008 Feb;53(2):175-86. doi: 10.1016/j.archoralbio.2007.09.010. Epub 2007 Nov 9.
• [14] Matrix metalloproteinases in emphysema.Matrix Biol. 2018 Nov;73:34-51. doi: 10.1016/j.matbio.2018.01.018. Epub 2018 Mar 23.
• [15] Overexpression of MMP21 and MMP28 is associated with gastric cancer progression and poor prognosis.Oncol Lett. 2018 May;15(5):7776-7782. doi: 10.3892/ol.2018.8328. Epub 2018 Mar 22.
• [16] Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes.Dis Model Mech. 2017 May 1;10(5):559-579. doi: 10.1242/dmm.027730. Epub 2017 Jan 18.
• [17] Infliximab restores the dysfunctional matrix remodeling protein and growth factor gene expression in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2014 Feb;20(2):339-52. doi: 10.1097/01.MIB.0000438430.15553.90.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [22] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [25] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [26] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.