Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB10IJH)

• DOT Name: La-related protein 4 (LARP4)
• Synonyms: La ribonucleoprotein domain family member 4
• Gene Name: LARP4
• Related Disease:
  Bone osteosarcoma
  Epithelial ovarian cancer
  Neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Polycystic ovarian syndrome
  Advanced cancer
  Nasopharyngeal carcinoma
• UniProt ID: LARP4_HUMAN
• PDB ID: 2CQK; 3PKN; 6I9B
• Pfam ID: PF05383
• Sequence:
  MLLFVEQVASKGTGLNPNAKVWQEIAPGNTDATPVTHGTESSWHEIAATSGAHPEGNAEL
  SEDICKEYEVMYSSSCETTRNTTGIEESTDGMILGPEDLSYQIYDVSGESNSAVSTEDLK
  ECLKKQLEFCFSRENLSKDLYLISQMDSDQFIPIWTVANMEEIKKLTTDPDLILEVLRSS
  PMVQVDEKGEKVRPSHKRCIVILREIPETTPIEEVKGLFKSENCPKVISCEFAHNSNWYI
  TFQSDTDAQQAFKYLREEVKTFQGKPIMARIKAINTFFAKNGYRLMDSSIYSHPIQTQAQ
  YASPVFMQPVYNPHQQYSVYSIVPQSWSPNPTPYFETPLAPFPNGSFVNGFNSPGSYKTN
  AAAMNMGRPFQKNRVKPQFRSSGGSEHSTEGSVSLGDGQLNRYSSRNFPAERHNPTVTGH
  QEQTYLQKETSTLQVEQNGDYGRGRRTLFRGRRRREDDRISRPHPSTAESKAPTPKFDLL
  ASNFPPLPGSSSRMPGELVLENRMSDVVKGVYKEKDNEELTISCPVPADEQTECTSAQQL
  NMSTSSPCAAELTALSTTQQEKDLIEDSSVQKDGLNQTTIPVSPPSTTKPSRASTASPCN
  NNINAATAVALQEPRKLSYAEVCQKPPKEPSSVLVQPLRELRSNVVSPTKNEDNGAPENS
  VEKPHEKPEARASKDYSGFRGNIIPRGAAGKIREQRRQFSHRAIPQGVTRRNGKEQYVPP
  RSPK
• Function: RNA binding protein that binds to the poly-A tract of mRNA molecules. Associates with the 40S ribosomal subunit and with polysomes. Plays a role in the regulation of mRNA translation. Plays a role in the regulation of cell morphology and cytoskeletal organization.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[5]

14 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 La-related protein 4 (LARP4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of La-related protein 4 (LARP4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of La-related protein 4 (LARP4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of La-related protein 4 (LARP4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of La-related protein 4 (LARP4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of La-related protein 4 (LARP4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of La-related protein 4 (LARP4).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of La-related protein 4 (LARP4).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of La-related protein 4 (LARP4).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of La-related protein 4 (LARP4).	[15]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of La-related protein 4 (LARP4).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of La-related protein 4 (LARP4).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of La-related protein 4 (LARP4).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of La-related protein 4 (LARP4).	[22]

4 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 affects the methylation of La-related protein 4 (LARP4).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of La-related protein 4 (LARP4).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of La-related protein 4 (LARP4).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of La-related protein 4 (LARP4).	[20]

References

• [1] Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA-424 in osteosarcoma.J Clin Lab Anal. 2020 Feb;34(2):e23045. doi: 10.1002/jcla.23045. Epub 2019 Oct 22.
• [2] La-Related Protein 4 as a Suppressor for Motility of Ovarian Cancer Cells.Tohoku J Exp Med. 2019 Jan;247(1):59-67. doi: 10.1620/tjem.247.59.
• [3] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [4] The RNA-binding protein LARP4 regulates cancer cell migration and invasion.Cytoskeleton (Hoboken). 2016 Nov;73(11):680-690. doi: 10.1002/cm.21336. Epub 2016 Sep 26.
• [5] Circular RNA_LARP4 inhibits cell proliferation and invasion of nasopharyngeal carcinoma by repressing ROCK1.Eur Rev Med Pharmacol Sci. 2019 Nov;23(22):9915-9922. doi: 10.26355/eurrev_201911_19557.
• [6] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] 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.
• [12] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [17] 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.
• [18] 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.
• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] 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.
• [21] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [22] 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.