Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOC223Z)

• DOT Name: Rho-related GTP-binding protein Rho6 (RND1)
• Synonyms: Rho family GTPase 1; Rnd1
• Gene Name: RND1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Triple negative breast cancer
  Advanced cancer
  Hepatocellular carcinoma
  Neoplasm
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: RND1_HUMAN
• PDB ID: 2CLS; 2REX; 3Q3J
• Pfam ID: PF00071
• Sequence:
  MKERRAPQPVVARCKLVLVGDVQCGKTAMLQVLAKDCYPETYVPTVFENYTACLETEEQR
  VELSLWDTSGSPYYDNVRPLCYSDSDAVLLCFDISRPETVDSALKKWRTEILDYCPSTRV
  LLIGCKTDLRTDLSTLMELSHQKQAPISYEQGCAIAKQLGAEIYLEGSAFTSEKSIHSIF
  RTASMLCLNKPSPLPQKSPVRSLSKRLLHLPSRSELISSTFKKEKAKSCSIM
• Function: Lacks intrinsic GTPase activity. Has a low affinity for GDP, and constitutively binds GTP. Controls rearrangements of the actin cytoskeleton. Induces the Rac-dependent neuritic process formation in part by disruption of the cortical actin filaments. Causes the formation of many neuritic processes from the cell body with disruption of the cortical actin filaments.
• Tissue Specificity: Mostly expressed in brain and liver.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Sema4D mediated inhibition of cell attachment and migration (R-HSA-416550)
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  RND1 GTPase cycle (R-HSA-9696273)
  SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion (R-HSA-399955)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Definitive	Genetic Variation	[1]
Breast neoplasm	DISNGJLM	Definitive	Altered Expression	[1]
Triple negative breast cancer	DISAMG6N	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[15]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[23]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Rho-related GTP-binding protein Rho6 (RND1).	[24]

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 decreases the methylation of Rho-related GTP-binding protein Rho6 (RND1).	[17]

References

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• [2] The Rho GTPase Rnd1 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma and is a favorable anti-metastasis target.Cell Death Dis. 2018 May 1;9(5):486. doi: 10.1038/s41419-018-0517-x.
• [3] The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis.Int J Mol Sci. 2019 Jul 24;20(15):3612. doi: 10.3390/ijms20153612.
• [4] RND1 regulates migration of human glioblastoma stem-like cells according to their anatomical localization and defines a prognostic signature in glioblastoma.Oncotarget. 2018 Sep 18;9(73):33788-33803. doi: 10.18632/oncotarget.26082. eCollection 2018 Sep 18.
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• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] 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.
• [13] 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.
• [14] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009 Mar 4;28(5):523-32.
• [17] 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.
• [18] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [24] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.