Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0BUA12)

• DOT Name: Small ribosomal subunit protein uS8 (RPS15A)
• Synonyms: 40S ribosomal protein S15a
• Gene Name: RPS15A
• Related Disease:
  Adult glioblastoma
  Diamond-Blackfan anemia 6
  Glioblastoma multiforme
  Acute myelogenous leukaemia
  Brain cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Kidney cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Renal carcinoma
  Renal cell carcinoma
  Bone osteosarcoma
  Colorectal carcinoma
  Lung adenocarcinoma
  Lung cancer
  Metastatic malignant neoplasm
  Osteosarcoma
  Diamond-Blackfan anemia
  Advanced cancer
  Diamond-Blackfan anemia 20
  Gastric cancer
  Pancreatic cancer
  Stomach cancer
• UniProt ID: RS15A_HUMAN
• PDB ID: 4UG0 ; 4V6X ; 5A2Q ; 5AJ0 ; 5FLX ; 5LKS ; 5OA3 ; 5T2C ; 5VYC ; 6FEC ; 6G18 ; 6G4S ; 6G4W ; 6G51 ; 6G53 ; 6G5H ; 6G5I ; 6IP5 ; 6IP6 ; 6IP8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6YBW ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZLW ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 6ZMT ; 6ZMW ; 6ZN5 ; 6ZOJ ; 6ZOK ; 6ZON ; 6ZP4 ; 6ZUO ; 6ZV6 ; 6ZVH ; 6ZVJ ; 6ZXD ; 6ZXE ; 6ZXF ; 6ZXG ; 6ZXH ; 7A09 ; 7K5I ; 7MQ8 ; 7MQ9 ; 7MQA ; 7QP6 ; 7QP7 ; 7R4X ; 7TQL ; 7WTS ; 7WTT ; 7WTU ; 7WTV ; 7WTW ; 7WTX ; 7WTZ ; 7WU0 ; 7XNX ; 7XNY ; 8G5Y ; 8G5Z ; 8G60 ; 8G61 ; 8G6J ; 8GLP ; 8JDJ ; 8JDK ; 8JDL ; 8JDM ; 8PPK ; 8PPL ; 8T4S
• Pfam ID: PF00410
• Sequence:
  MVRMNVLADALKSINNAEKRGKRQVLIRPCSKVIVRFLTVMMKHGYIGEFEIIDDHRAGK
  IVVNLTGRLNKCGVISPRFDVQLKDLEKWQNNLLPSRQFGFIVLTTSAGIMDHEEARRKH
  TGGKILGFFF
• Function: Component of the small ribosomal subunit. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Required for proper erythropoiesis.
• KEGG Pathway:
  Ribosome (hsa03010)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Peptide chain elongation (R-HSA-156902)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)
  Viral mRNA Translation (R-HSA-192823)
  Selenocysteine synthesis (R-HSA-2408557)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Eukaryotic Translation Termination (R-HSA-72764)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  SARS-CoV-1 modulates host translation machinery (R-HSA-9735869)
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Diamond-Blackfan anemia 6	DIS4FKKF	Definitive	GermlineCausalMutation	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Brain cancer	DISBKFB7	Strong	Altered Expression	[4]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Kidney cancer	DISBIPKM	Strong	Genetic Variation	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[13]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[9]
Lung cancer	DISCM4YA	moderate	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[14]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[12]
Diamond-Blackfan anemia	DISI2SNW	Supportive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[6]
Diamond-Blackfan anemia 20	DIS83XBL	Limited	Autosomal dominant	[15]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[16]
Pancreatic cancer	DISJC981	Limited	Biomarker	[17]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Small ribosomal subunit protein uS8 (RPS15A) decreases the response to substance of Artesunate.	[32]

13 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 Small ribosomal subunit protein uS8 (RPS15A).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Small ribosomal subunit protein uS8 (RPS15A).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[24]
Nabiximols	DMHKJ5I	Phase 3	Nabiximols increases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[25]
ACYLINE	DM9GRTK	Phase 2	ACYLINE increases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Small ribosomal subunit protein uS8 (RPS15A).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Small ribosomal subunit protein uS8 (RPS15A).	[31]

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 Small ribosomal subunit protein uS8 (RPS15A).	[27]

References

• [1] Down-regulation of ribosomal protein S15A inhibits proliferation of human glioblastoma cells in vivo and in vitro via AKT pathway.Tumour Biol. 2016 Apr;37(4):4979-90. doi: 10.1007/s13277-015-4323-0. Epub 2015 Nov 4.
• [2] Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia. Haematologica. 2017 Mar;102(3):e93-e96. doi: 10.3324/haematol.2016.153932. Epub 2016 Dec 1.
• [3] shRNA-mediated RPS15A silencing inhibits U937 acute myeloid leukemia cell proliferation and enhances apoptosis.Mol Med Rep. 2016 May;13(5):4400-6. doi: 10.3892/mmr.2016.5064. Epub 2016 Mar 30.
• [4] Knockdown of ribosomal protein S15A induces human glioblastoma cell apoptosis.World J Surg Oncol. 2016 Apr 29;14:129. doi: 10.1186/s12957-016-0891-8.
• [5] Ribosomal protein small subunit 15A (RPS15A) inhibits the apoptosis of breast cancer MDA-MB-231 cells via upregulating phosphorylated ERK1/2, Bad, and Chk1.J Cell Biochem. 2020 Jan;121(1):587-595. doi: 10.1002/jcb.29304. Epub 2019 Sep 18.
• [6] Knockdown of ribosomal protein S15A inhibits human kidney cancer cell growth invitro and invivo.Mol Med Rep. 2019 Feb;19(2):1117-1127. doi: 10.3892/mmr.2018.9751. Epub 2018 Dec 12.
• [7] Human S15a expression is upregulated by hepatitis B virus X protein.Mol Carcinog. 2004 May;40(1):34-46. doi: 10.1002/mc.20012.
• [8] Ribosomal proteins: insight into molecular roles and functions in hepatocellular carcinoma.Oncogene. 2018 Jan 18;37(3):277-285. doi: 10.1038/onc.2017.343. Epub 2017 Sep 25.
• [9] Decreased expression of RPS15A suppresses proliferation of lung cancer cells.Tumour Biol. 2015 Sep;36(9):6733-40. doi: 10.1007/s13277-015-3371-9. Epub 2015 Apr 3.
• [10] Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/-catenin-induced FGF18 expression in hepatocellular carcinoma.Oncogene. 2018 Mar;37(9):1220-1236. doi: 10.1038/s41388-017-0017-y. Epub 2017 Dec 15.
• [11] MicroRNA-147b suppresses the proliferation and invasion of non-small-cell lung cancer cells through downregulation of Wnt/-catenin signalling via targeting of RPS15A.Clin Exp Pharmacol Physiol. 2020 Mar;47(3):449-458. doi: 10.1111/1440-1681.13203. Epub 2019 Nov 24.
• [12] Ribosomal protein S15A augments human osteosarcoma cell proliferation in vitro.Cancer Biother Radiopharm. 2014 Dec;29(10):451-6. doi: 10.1089/cbr.2014.1698.
• [13] Downregulation of RPS15A by miR-29a-3p attenuates cell proliferation in colorectal carcinoma.Biosci Biotechnol Biochem. 2019 Nov;83(11):2057-2064. doi: 10.1080/09168451.2019.1637712. Epub 2019 Jul 13.
• [14] Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway.Int J Oncol. 2016 Apr;48(4):1628-38. doi: 10.3892/ijo.2016.3366. Epub 2016 Feb 1.
• [15] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [16] RPS15A promotes gastric cancer progression via activation of the Akt/IKK-/NF-B signalling pathway.J Cell Mol Med. 2019 Mar;23(3):2207-2218. doi: 10.1111/jcmm.14141. Epub 2019 Jan 19.
• [17] Overexpression of microRNA-519d-3p suppressed the growth of pancreatic cancer cells by inhibiting ribosomal protein S15A-mediated Wnt/-catenin signaling.Chem Biol Interact. 2019 May 1;304:1-9. doi: 10.1016/j.cbi.2019.02.026. Epub 2019 Mar 1.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [20] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [21] 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.
• [22] [Construction of subtracted cDNA library in human Jurkat T cell line induced by arsenic trioxide in vitro]. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 Nov;37(6):403-7.
• [23] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [24] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [25] Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur J Neurol. 2018 Jul;25(7):934-e70. doi: 10.1111/ene.13623. Epub 2018 Apr 16.
• [26] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [27] 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.
• [28] 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.
• [29] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [30] 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.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.