Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSS8XR6)

• DOT Name: Rhotekin (RTKN)
• Gene Name: RTKN
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Gastric adenocarcinoma
  Glioblastoma multiforme
  Neoplasm
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Gastric cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Stomach cancer
• UniProt ID: RTKN_HUMAN
• Pfam ID: PF08174 ; PF00169
• Sequence:
  MFSRNHRSRVTVARGSALEMEFKRGRFRLSLFSDLPEDTELQRKLDHEIRMREGACKLLA
  ACSQREQALEATKSLLVCNSRILSYMGELQRRKEAQVLGKTSRRPSDSGPPAERSPCRGR
  VCISDLRIPLMWKDTEYFKNKGDLHRWAVFLLLQLGEHIQDTEMILVDRTLTDISFQSNV
  LFAEAGPDFELRLELYGACVEEEGALTGGPKRLATKLSSSLGRSSGRRVRASLDSAGGSG
  SSPILLPTPVVGGPRYHLLAHTTLTLAAVQDGFRTHDLTLASHEENPAWLPLYGSVCCRL
  AAQPLCMTQPTASGTLRVQQAGEMQNWAQVHGVLKGTNLFCYRQPEDADTGEEPLLTIAV
  NKETRVRAGELDQALGRPFTLSISNQYGDDEVTHTLQTESREALQSWMEALWQLFFDMSQ
  WKQCCDEIMKIETPAPRKPPQALAKQGSLYHEMAIEPLDDIAAVTDILTQREGARLETPP
  PWLAMFTDQPALPNPCSPASVAPAPDWTHPLPWGRPRTFSLDAVPPDHSPRARSVAPLPP
  QRSPRTRGLCSKGQPRTWLQSPV
• Function: Mediates Rho signaling to activate NF-kappa-B and may confer increased resistance to apoptosis to cells in gastric tumorigenesis. May play a novel role in the organization of septin structures.
• Tissue Specificity: Highly expressed in prostate, moderately in kidney, heart, brain, spleen, testis, placenta, small intestine, pancreas, skeletal muscle and peripheral blood leukocytes, and weakly in ovary, colon and thymus. Weakly expressed in all normal cell lines tested. Overexpressed in various cancer cell lines.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  RHO GTPases Activate Rhotekin and Rhophilins (R-HSA-5666185)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	moderate	Biomarker	[6]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[2]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[5]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[7]
Lung cancer	DISCM4YA	Limited	Biomarker	[7]
Lung carcinoma	DISTR26C	Limited	Biomarker	[7]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[5]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Rhotekin (RTKN) decreases the response to substance of Fluorouracil.	[21]
Paclitaxel	DMLB81S	Approved	Rhotekin (RTKN) decreases the response to substance of Paclitaxel.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Rhotekin (RTKN).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rhotekin (RTKN).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rhotekin (RTKN).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rhotekin (RTKN).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rhotekin (RTKN).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rhotekin (RTKN).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rhotekin (RTKN).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rhotekin (RTKN).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rhotekin (RTKN).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rhotekin (RTKN).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Rhotekin (RTKN).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rhotekin (RTKN).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rhotekin (RTKN).	[20]

References

• [1] Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma.Oncogene. 2014 Mar 20;33(12):1558-69. doi: 10.1038/onc.2013.97. Epub 2013 Apr 8.
• [2] MicroRNA-152 inhibits tumor cell growth by directly targeting RTKN in hepatocellular carcinoma.Oncol Rep. 2017 Feb;37(2):1227-1234. doi: 10.3892/or.2016.5290. Epub 2016 Dec 5.
• [3] miR-145 inhibits breast cancer cell growth through RTKN.Int J Oncol. 2009 May;34(5):1461-6.
• [4] Overexpression of rho effector rhotekin confers increased survival in gastric adenocarcinoma.J Biomed Sci. 2004 Sep-Oct;11(5):661-70. doi: 10.1007/BF02256132.
• [5] Expression and biological function of rhotekin in gastric cancer through regulating p53 pathway.Cancer Manag Res. 2019 Jan 25;11:1069-1080. doi: 10.2147/CMAR.S185345. eCollection 2019.
• [6] RETRACTED: Long non-coding RNA HULC interacts with miR-613 to regulate colon cancer growth and metastasis through targeting RTKN.Biomed Pharmacother. 2019 Jan;109:2035-2042. doi: 10.1016/j.biopha.2018.08.017. Epub 2018 Nov 26.
• [7] Inhibition of rhotekin exhibits antitumor effects in lung cancer cells.Oncol Rep. 2016 May;35(5):2529-34. doi: 10.3892/or.2016.4634. Epub 2016 Feb 24.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] 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.
• [21] Rho/Rhotekin-mediated NF-kappaB activation confers resistance to apoptosis. Oncogene. 2004 Nov 18;23(54):8731-42. doi: 10.1038/sj.onc.1208106.