Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0ZE01B)

• DOT Name: Actin-related protein 2/3 complex subunit 4 (ARPC4)
• Synonyms: Arp2/3 complex 20 kDa subunit; p20-ARC
• Gene Name: ARPC4
• Related Disease:
  Colorectal carcinoma
  Developmental delay, language impairment, and ocular abnormalities
  Pancreatic cancer
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: ARPC4_HUMAN
• PDB ID: 6UHC; 6YW6; 6YW7
• Pfam ID: PF05856
• Sequence:
  MTATLRPYLSAVRATLQAALCLENFSSQVVERHNKPEVEVRSSKELLLQPVTISRNEKEK
  VLIEGSINSVRVSIAVKQADEIEKILCHKFMRFMMMRAENFFILRRKPVEGYDISFLITN
  FHTEQMYKHKLVDFVIHFMEEIDKEISEMKLSVNARARIVAEEFLKNF
• 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. 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Developmental delay, language impairment, and ocular abnormalities	DISIPV5F	Strong	Autosomal dominant	[2]
Pancreatic cancer	DISJC981	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Limited	Altered Expression	[4]
Urinary bladder cancer	DISDV4T7	Limited	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Actin-related protein 2/3 complex subunit 4 (ARPC4) affects the response to substance of Acetaminophen.	[15]

11 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 Actin-related protein 2/3 complex subunit 4 (ARPC4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[13]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Actin-related protein 2/3 complex subunit 4 (ARPC4).	[14]

References

• [1] Short interfering RNA-mediated silencing of actin-related protein 2/3 complex subunit 4 inhibits the migration of SW620 human colorectal cancer cells.Oncol Lett. 2018 Mar;15(3):2847-2854. doi: 10.3892/ol.2017.7642. Epub 2017 Dec 19.
• [2] A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes microcephaly and speech delay. HGG Adv. 2021 Nov 25;3(1):100072. doi: 10.1016/j.xhgg.2021.100072. eCollection 2022 Jan 13.
• [3] Silencing of the ARP2/3 complex disturbs pancreatic cancer cell migration.Anticancer Res. 2013 Jan;33(1):45-52.
• [4] ARPC4 promotes bladder cancer cell invasion and is associated with lymph node metastasis.J Cell Biochem. 2020 Jan;121(1):231-243. doi: 10.1002/jcb.29136. Epub 2019 Jun 12.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] 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.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [14] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [15] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.