Details of Drug Off-Target (DOT)

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

• DOT Name: Actin-related protein 2/3 complex subunit 2 (ARPC2)
• Synonyms: Arp2/3 complex 34 kDa subunit; p34-ARC
• Gene Name: ARPC2
• Related Disease:
  Neoplasm
  Ulcerative colitis
  Breast cancer
  Breast carcinoma
  Epilepsy
  Gastric cancer
  Inflammatory bowel disease
  Stomach cancer
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Metastatic malignant neoplasm
• UniProt ID: ARPC2_HUMAN
• PDB ID: 6UHC; 6YW6; 6YW7
• Pfam ID: PF04045
• Sequence:
  MILLEVNNRIIEETLALKFENAAAGNKPEAVEVTFADFDGVLYHISNPNGDKTKVMVSIS
  LKFYKELQAHGADELLKRVYGSFLVNPESGYNVSLLYDLENLPASKDSIVHQAGMLKRNC
  FASVFEKYFQFQEEGKEGENRAVIHYRDDETMYVESKKDRVTVVFSTVFKDDDDVVIGKV
  FMQEFKEGRRASHTAPQVLFSHREPPLELKDTDAAVGDNIGYITFVLFPRHTNASARDNT
  INLIHTFRDYLHYHIKCSKAYIHTRMRAKTSDFLKVLNRARPDAEKKEMKTITGKTFSSR
• Function: Actin-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. Seems to contact the mother actin filament. In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs).
• KEGG Pathway:
  Endocytosis (hsa04144)
  Tight junction (hsa04530)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Ulcerative colitis	DIS8K27O	Definitive	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Epilepsy	DISBB28L	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Colon cancer	DISVC52G	Limited	Biomarker	[7]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[20]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[21]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[22]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Actin-related protein 2/3 complex subunit 2 (ARPC2).	[18]

References

• [1] ARPC2 promotes breast cancer proliferation and metastasis.Oncol Rep. 2019 Jun;41(6):3189-3200. doi: 10.3892/or.2019.7113. Epub 2019 Apr 12.
• [2] Genetic analysis in a Dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk.Am J Gastroenterol. 2010 Feb;105(2):395-402. doi: 10.1038/ajg.2009.576. Epub 2009 Oct 27.
• [3] RBM3 upregulates ARPC2 by binding the 3'UTR and contributes to breast cancer progression.Int J Oncol. 2019 Apr;54(4):1387-1397. doi: 10.3892/ijo.2019.4698. Epub 2019 Jan 28.
• [4] Overexpression of N-WASP in the brain of human epilepsy.Brain Res. 2008 Oct 3;1233:168-75. doi: 10.1016/j.brainres.2008.07.101. Epub 2008 Aug 5.
• [5] Role of ARPC2 in Human Gastric Cancer.Mediators Inflamm. 2017;2017:5432818. doi: 10.1155/2017/5432818. Epub 2017 Jun 13.
• [6] Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility.Nat Genet. 2008 Nov;40(11):1319-23. doi: 10.1038/ng.221. Epub 2008 Oct 5.
• [7] Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex.Cancer Sci. 2019 Dec;110(12):3788-3801. doi: 10.1111/cas.14205. Epub 2019 Nov 15.
• [8] 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.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [15] 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.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [18] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [19] 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.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [22] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [23] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.