General Information of Drug Off-Target (DOT) (ID: OTVMOB3F)

DOT Name Protein S100-A8 (S100A8)
Synonyms
Calgranulin-A; Calprotectin L1L subunit; Cystic fibrosis antigen; CFAG; Leukocyte L1 complex light chain; Migration inhibitory factor-related protein 8; MRP-8; p8; S100 calcium-binding protein A8; Urinary stone protein band A
Gene Name S100A8
UniProt ID
S10A8_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1MR8; 1XK4; 4GGF; 4XJK; 5HLO; 5HLV; 5W1F; 6DS2; 7QUV
Pfam ID
PF01023
Sequence
MLTELEKALNSIIDVYHKYSLIKGNFHAVYRDDLKKLLETECPQYIRKKGADVWFKELDI
NTDGAVNFQEFLILVIKMGVAAHKKSHEESHKE
Function
S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity; (Microbial infection) Upon infection by human coronavirus SARS-CoV-2, may induce expansion of aberrant immature neutrophils in a TLR4-dependent manner.
Tissue Specificity
Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn's disease, giant cell arteritis, cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers.
KEGG Pathway
IL-17 sig.ling pathway (hsa04657 )
Reactome Pathway
MyD88 (R-HSA-166058 )
MyD88 deficiency (TLR2/4) (R-HSA-5602498 )
IRAK4 deficiency (TLR2/4) (R-HSA-5603041 )
RHO GTPases Activate NADPH Oxidases (R-HSA-5668599 )
Regulation of TLR by endogenous ligand (R-HSA-5686938 )
Neutrophil degranulation (R-HSA-6798695 )
Metal sequestration by antimicrobial proteins (R-HSA-6799990 )
ER-Phagosome pathway (R-HSA-1236974 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
35 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 Protein S100-A8 (S100A8). [1]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Protein S100-A8 (S100A8). [2]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Protein S100-A8 (S100A8). [3]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Protein S100-A8 (S100A8). [4]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Protein S100-A8 (S100A8). [5]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Protein S100-A8 (S100A8). [6]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of Protein S100-A8 (S100A8). [7]
Calcitriol DM8ZVJ7 Approved Calcitriol decreases the expression of Protein S100-A8 (S100A8). [8]
Decitabine DMQL8XJ Approved Decitabine affects the expression of Protein S100-A8 (S100A8). [9]
Marinol DM70IK5 Approved Marinol decreases the expression of Protein S100-A8 (S100A8). [10]
Phenobarbital DMXZOCG Approved Phenobarbital increases the expression of Protein S100-A8 (S100A8). [11]
Dexamethasone DMMWZET Approved Dexamethasone increases the expression of Protein S100-A8 (S100A8). [12]
Isotretinoin DM4QTBN Approved Isotretinoin increases the expression of Protein S100-A8 (S100A8). [3]
Troglitazone DM3VFPD Approved Troglitazone increases the expression of Protein S100-A8 (S100A8). [11]
Diclofenac DMPIHLS Approved Diclofenac increases the expression of Protein S100-A8 (S100A8). [11]
Simvastatin DM30SGU Approved Simvastatin increases the expression of Protein S100-A8 (S100A8). [13]
Alitretinoin DMME8LH Approved Alitretinoin decreases the expression of Protein S100-A8 (S100A8). [3]
Pioglitazone DMKJ485 Approved Pioglitazone decreases the expression of Protein S100-A8 (S100A8). [14]
Mebendazole DMO14SG Approved Mebendazole increases the expression of Protein S100-A8 (S100A8). [15]
Flutamide DMK0O7U Approved Flutamide increases the expression of Protein S100-A8 (S100A8). [11]
Norepinephrine DMOUC09 Approved Norepinephrine increases the expression of Protein S100-A8 (S100A8). [16]
Primidone DM0WX6I Approved Primidone increases the expression of Protein S100-A8 (S100A8). [11]
Halothane DM80OZ5 Approved Halothane increases the expression of Protein S100-A8 (S100A8). [11]
Dicloxacillin DM8EU0Z Approved Dicloxacillin increases the expression of Protein S100-A8 (S100A8). [11]
Tamibarotene DM3G74J Phase 3 Tamibarotene increases the expression of Protein S100-A8 (S100A8). [17]
Seocalcitol DMKL9QO Phase 3 Seocalcitol decreases the expression of Protein S100-A8 (S100A8). [18]
Coprexa DMA0WEK Phase 3 Coprexa increases the expression of Protein S100-A8 (S100A8). [19]
Genistein DM0JETC Phase 2/3 Genistein decreases the expression of Protein S100-A8 (S100A8). [20]
phorbol 12-myristate 13-acetate DMJWD62 Phase 2 phorbol 12-myristate 13-acetate increases the expression of Protein S100-A8 (S100A8). [12]
Sulforaphane DMQY3L0 Investigative Sulforaphane increases the expression of Protein S100-A8 (S100A8). [22]
chloropicrin DMSGBQA Investigative chloropicrin affects the expression of Protein S100-A8 (S100A8). [23]
Paraquat DMR8O3X Investigative Paraquat decreases the expression of Protein S100-A8 (S100A8). [24]
D-glucose DMMG2TO Investigative D-glucose increases the expression of Protein S100-A8 (S100A8). [25]
Phencyclidine DMQBEYX Investigative Phencyclidine increases the expression of Protein S100-A8 (S100A8). [26]
all-trans-4-oxo-retinoic acid DMM2R1N Investigative all-trans-4-oxo-retinoic acid increases the expression of Protein S100-A8 (S100A8). [3]
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⏷ Show the Full List of 35 Drug(s)
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 increases the methylation of Protein S100-A8 (S100A8). [21]
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References

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10 Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
11 Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. 2017 Jul;37(7):863-872. doi: 10.1002/jat.3435. Epub 2017 Jan 31.
12 1 alpha,25-(OH)2 vitamin D3 enhances expression of the genes encoding Ca(2+)-binding proteins MRP-8 and MRP-14. Am J Physiol. 1992 Jan;262(1 Pt 1):C235-42. doi: 10.1152/ajpcell.1992.262.1.C235.
13 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.
14 Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
15 Development of a cell-based assay system considering drug metabolism and immune- and inflammatory-related factors for the risk assessment of drug-induced liver injury. Toxicol Lett. 2014 Jul 3;228(1):13-24. doi: 10.1016/j.toxlet.2014.04.005. Epub 2014 Apr 15.
16 Norepinephrine stimulates calprotectin expression in human monocytic cells. J Periodontal Res. 2006 Jun;41(3):159-64. doi: 10.1111/j.1600-0765.2005.00845.x.
17 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
18 Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
19 Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
20 Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
21 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.
22 Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
23 Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
24 CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
25 Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes. 2010 Jan;59(1):249-55. doi: 10.2337/db09-0801. Epub 2009 Oct 15.
26 Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.