Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT68R6IO)

• DOT Name: Prospero homeobox protein 1 (PROX1)
• Synonyms: Homeobox prospero-like protein PROX1; PROX-1
• Gene Name: PROX1
• Related Disease:
  Adult glioblastoma
  Brain neoplasm
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Liver cirrhosis
  Neuroblastoma
  Prostate cancer
  Prostate carcinoma
  Adenoma
  Advanced cancer
  Arteriosclerosis
  Astrocytoma
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Carcinoma of esophagus
  Cholangiocarcinoma
  Colon cancer
  Colon carcinoma
  Corneal neovascularization
  Crohn disease
  Esophageal cancer
  Glioma
  Hepatocellular carcinoma
  Intestinal neoplasm
  Kaposi sarcoma
  Medullary thyroid gland carcinoma
  Metastatic malignant neoplasm
  Myocardial infarction
  Neoplasm of esophagus
  Obesity
  Pancreatic cancer
  Squamous cell carcinoma
  Thyroid gland carcinoma
  Thyroid gland follicular carcinoma
  Hepatitis B virus infection
  Small-cell lung cancer
  Thyroid gland papillary carcinoma
  Gastric cancer
  Hyperglycemia
  Non-insulin dependent diabetes
  Status epilepticus seizure
  Stomach cancer
  Thyroid cancer
  Thyroid tumor
  Type-1/2 diabetes
• UniProt ID: PROX1_HUMAN
• PDB ID: 2LMD
• Pfam ID: PF05044
• Sequence:
  MPDHDSTALLSRQTKRRRVDIGVKRTVGTASAFFAKARATFFSAMNPQGSEQDVEYSVVQ
  HADGEKSNVLRKLLKRANSYEDAMMPFPGATIISQLLKNNMNKNGGTEPSFQASGLSSTG
  SEVHQEDICSNSSRDSPPECLSPFGRPTMSQFDMDRLCDEHLRAKRARVENIIRGMSHSP
  SVALRGNENEREMAPQSVSPRESYRENKRKQKLPQQQQQSFQQLVSARKEQKREERRQLK
  QQLEDMQKQLRQLQEKFYQIYDSTDSENDEDGNLSEDSMRSEILDARAQDSVGRSDNEMC
  ELDPGQFIDRARALIREQEMAENKPKREGNNKERDHGPNSLQPEGKHLAETLKQELNTAM
  SQVVDTVVKVFSAKPSRQVPQVFPPLQIPQARFAVNGENHNFHTANQRLQCFGDVIIPNP
  LDTFGNVQMASSTDQTEALPLVVRKNSSDQSASGPAAGGHHQPLHQSPLSATTGFTTSTF
  RHPFPLPLMAYPFQSPLGAPSGSFSGKDRASPESLDLTRDTTSLRTKMSSHHLSHHPCSP
  AHPPSTAEGLSLSLIKSECGDLQDMSEISPYSGSAMQEGLSPNHLKKAKLMFFYTRYPSS
  NMLKTYFSDVKFNRCITSQLIKWFSNFREFYYIQMEKYARQAINDGVTSTEELSITRDCE
  LYRALNMHYNKANDFEVPERFLEVAQITLREFFNAIIAGKDVDPSWKKAIYKVICKLDSE
  VPEIFKSPNCLQELLHE
• Function: Transcription factor involved in developmental processes such as cell fate determination, gene transcriptional regulation and progenitor cell regulation in a number of organs. Plays a critical role in embryonic development and functions as a key regulatory protein in neurogenesis and the development of the heart, eye lens, liver, pancreas and the lymphatic system. Involved in the regulation of the circadian rhythm. Represses: transcription of the retinoid-related orphan receptor RORG, transcriptional activator activity of RORA and RORG and the expression of RORA/G-target genes including core clock components: BMAL1, NPAS2 and CRY1 and metabolic genes: AVPR1A and ELOVL3.
• Tissue Specificity: Most actively expressed in the developing lens. Detected also in embryonic brain, lung, liver and kidney. In adult, it is more abundant in heart and liver than in brain, skeletal muscle, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Brain neoplasm	DISY3EKS	Definitive	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Liver cirrhosis	DIS4G1GX	Definitive	Biomarker	[4]
Neuroblastoma	DISVZBI4	Definitive	Altered Expression	[5]
Prostate cancer	DISF190Y	Definitive	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[6]
Adenoma	DIS78ZEV	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[8]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[9]
Astrocytoma	DISL3V18	Strong	Altered Expression	[10]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[11]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[11]
Breast neoplasm	DISNGJLM	Strong	Posttranslational Modification	[12]
Carcinoma	DISH9F1N	Strong	Biomarker	[13]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[14]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[15]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[15]
Corneal neovascularization	DISKOGZP	Strong	Biomarker	[16]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[17]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[14]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[18]
Intestinal neoplasm	DISK0GUH	Strong	Biomarker	[19]
Kaposi sarcoma	DISC1H1Z	Strong	Biomarker	[20]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Altered Expression	[21]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[15]
Myocardial infarction	DIS655KI	Strong	Biomarker	[22]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[14]
Obesity	DIS47Y1K	Strong	Genetic Variation	[23]
Pancreatic cancer	DISJC981	Strong	Biomarker	[24]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[25]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[26]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Biomarker	[25]
Hepatitis B virus infection	DISLQ2XY	moderate	Altered Expression	[18]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[27]
Thyroid gland papillary carcinoma	DIS48YMM	moderate	Altered Expression	[26]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[28]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[29]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[30]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[31]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[28]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[32]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[32]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[33]

20 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 Prospero homeobox protein 1 (PROX1).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Prospero homeobox protein 1 (PROX1).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Prospero homeobox protein 1 (PROX1).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prospero homeobox protein 1 (PROX1).	[37]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Prospero homeobox protein 1 (PROX1).	[35]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Prospero homeobox protein 1 (PROX1).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Prospero homeobox protein 1 (PROX1).	[39]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Prospero homeobox protein 1 (PROX1).	[40]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Prospero homeobox protein 1 (PROX1).	[41]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Prospero homeobox protein 1 (PROX1).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Prospero homeobox protein 1 (PROX1).	[43]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Prospero homeobox protein 1 (PROX1).	[44]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Prospero homeobox protein 1 (PROX1).	[45]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Prospero homeobox protein 1 (PROX1).	[46]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Prospero homeobox protein 1 (PROX1).	[47]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prospero homeobox protein 1 (PROX1).	[35]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Prospero homeobox protein 1 (PROX1).	[48]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Prospero homeobox protein 1 (PROX1).	[52]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Prospero homeobox protein 1 (PROX1).	[53]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Prospero homeobox protein 1 (PROX1).	[54]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Prospero homeobox protein 1 (PROX1).	[49]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Prospero homeobox protein 1 (PROX1).	[50]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Prospero homeobox protein 1 (PROX1).	[51]

References

• [1] Reduced Expression of PROX1 Transitions Glioblastoma Cells into a Mesenchymal Gene Expression Subtype.Cancer Res. 2018 Oct 15;78(20):5901-5916. doi: 10.1158/0008-5472.CAN-18-0320. Epub 2018 Aug 22.
• [2] PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status.Oncotarget. 2016 Nov 8;7(45):72431-72442. doi: 10.18632/oncotarget.11957.
• [3] Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1 Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma.Ann Surg Oncol. 2015 Dec;22 Suppl 3:S1566-73. doi: 10.1245/s10434-015-4831-6. Epub 2015 Aug 27.
• [4] Altered regulation of Prox1-gene-expression in liver tumors.BMC Cancer. 2008 Apr 9;8:92. doi: 10.1186/1471-2407-8-92.
• [5] Prox1 suppresses the proliferation of neuroblastoma cells via a dual action in p27-Kip1 and Cdc25A.Oncogene. 2013 Feb 21;32(8):947-60. doi: 10.1038/onc.2012.129. Epub 2012 Apr 16.
• [6] DAB2IP regulates EMT and metastasis of prostate cancer through targeting PROX1 transcription and destabilizing HIF1 protein.Cell Signal. 2016 Nov;28(11):1623-30. doi: 10.1016/j.cellsig.2016.07.011. Epub 2016 Jul 27.
• [7] Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype.Cancer Cell. 2008 May;13(5):407-19. doi: 10.1016/j.ccr.2008.02.020.
• [8] Pheno-seq - linking visual features and gene expression in 3D cell culture systems.Sci Rep. 2019 Aug 26;9(1):12367. doi: 10.1038/s41598-019-48771-4.
• [9] SUMOylation-dependent LRH-1/PROX1 interaction promotes atherosclerosis by decreasing hepatic reverse cholesterol transport.Cell Metab. 2014 Oct 7;20(4):603-13. doi: 10.1016/j.cmet.2014.07.023. Epub 2014 Aug 28.
• [10] PROX1 promotes human glioblastoma cell proliferation and invasion via activation of the nuclear factor-B signaling pathway.Mol Med Rep. 2017 Feb;15(2):963-968. doi: 10.3892/mmr.2016.6075. Epub 2016 Dec 27.
• [11] Long non-coding RNA LINC00968 reduces cell proliferation and migration and angiogenesis in breast cancer through up-regulation of PROX1 by reducing hsa-miR-423-5p.Cell Cycle. 2019 Aug;18(16):1908-1924. doi: 10.1080/15384101.2019.1632641. Epub 2019 Jun 29.
• [12] Epigenetic silencing of the candidate tumor suppressor gene PROX1 in sporadic breast cancer. Int J Cancer. 2007 Aug 1;121(3):547-54. doi: 10.1002/ijc.22705.
• [13] Prospero-related homeobox 1 (PROX1) is frequently inactivated by genomic deletions and epigenetic silencing in carcinomas of the bilary system.J Hepatol. 2007 Jan;46(1):89-97. doi: 10.1016/j.jhep.2006.07.033. Epub 2006 Sep 27.
• [14] PROX1 Is Associated with Cancer Progression and Prognosis in Gastric Cancer.Anticancer Res. 2018 Nov;38(11):6139-6145. doi: 10.21873/anticanres.12966.
• [15] PROX1 promotes metabolic adaptation and fuels outgrowth of Wnt(high) metastatic colon cancer cells.Cell Rep. 2014 Sep 25;8(6):1957-1973. doi: 10.1016/j.celrep.2014.08.041. Epub 2014 Sep 18.
• [16] Limited versus total epithelial debridement ocular surface injury: Live fluorescence imaging of hemangiogenesis and lymphangiogenesis in Prox1-GFP/Flk1::Myr-mCherry mice.Biochim Biophys Acta. 2016 Oct;1860(10):2148-56. doi: 10.1016/j.bbagen.2016.05.027. Epub 2016 May 24.
• [17] Decreased Expression of Prox1 Is Associated With Postoperative Recurrence in Crohn's Disease.J Crohns Colitis. 2018 Nov 9;12(10):1210-1218. doi: 10.1093/ecco-jcc/jjy091.
• [18] Suppression of PROX1-mediated TERT expression in hepatitis B viral hepatocellular carcinoma.Int J Cancer. 2018 Dec 15;143(12):3155-3168. doi: 10.1002/ijc.31731. Epub 2018 Sep 27.
• [19] Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance.Cell Rep. 2014 Sep 25;8(6):1943-1956. doi: 10.1016/j.celrep.2014.08.034. Epub 2014 Sep 18.
• [20] Oroxylin A inhibits Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6-mediated lymphatic reprogramming of vascular endothelial cells through modulating PPAR/Prox1 axis.J Med Virol. 2019 Mar;91(3):463-472. doi: 10.1002/jmv.25337. Epub 2018 Nov 2.
• [21] Expression of Prox1 in Medullary Thyroid Carcinoma Is Associated with Chromogranin A and Calcitonin Expression and with Ki67 Proliferative Index, but Not with Prognosis.Endocr Pathol. 2019 Jun;30(2):138-145. doi: 10.1007/s12022-019-9576-5.
• [22] Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium.PLoS One. 2017 Mar 23;12(3):e0173927. doi: 10.1371/journal.pone.0173927. eCollection 2017.
• [23] Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians.Obesity (Silver Spring). 2013 Nov;21(11):2405-12. doi: 10.1002/oby.20153. Epub 2013 Jul 2.
• [24] Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread.Int J Oncol. 2006 Apr;28(4):883-90.
• [25] Transcription Factor Prospero Homeobox 1 (PROX1) as a Potential Angiogenic Regulator of Follicular Thyroid Cancer Dissemination.Int J Mol Sci. 2019 Nov 10;20(22):5619. doi: 10.3390/ijms20225619.
• [26] The role of prospero homeobox 1 (PROX1) expression in follicular thyroid carcinoma cells.Oncotarget. 2017 Dec 12;8(69):114136-114155. doi: 10.18632/oncotarget.23167. eCollection 2017 Dec 26.
• [27] Proliferation of small cell lung cancer cell line reduced by knocking-down PROX1 via shRNA in lentivirus.Anticancer Res. 2013 Aug;33(8):3169-75.
• [28] High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1.Cancer Med. 2019 Nov;8(16):6995-7005. doi: 10.1002/cam4.2576. Epub 2019 Sep 27.
• [29] Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine -Cells.Diabetes. 2016 Mar;65(3):687-98. doi: 10.2337/db15-0713. Epub 2015 Dec 2.
• [30] The Type 2 Diabetes Susceptibility PROX1 Gene Variants Are Associated with Postprandial Plasma Metabolites Profile in Non-Diabetic Men.Nutrients. 2019 Apr 19;11(4):882. doi: 10.3390/nu11040882.
• [31] Stereological methods reveal the robust size and stability of ectopic hilar granule cells after pilocarpine-induced status epilepticus in the adult rat.Eur J Neurosci. 2006 Oct;24(8):2203-10. doi: 10.1111/j.1460-9568.2006.05101.x. Epub 2006 Oct 17.
• [32] Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells.Cancer Res. 2016 Feb 1;76(3):582-93. doi: 10.1158/0008-5472.CAN-15-1199. Epub 2015 Nov 25.
• [33] Long noncoding RNA-antisense noncoding RNA in the INK4 locus accelerates wound healing in diabetes by promoting lymphangiogenesis via regulating miR-181a/Prox1 axis.J Cell Physiol. 2019 Apr;234(4):4627-4640. doi: 10.1002/jcp.27260. Epub 2018 Nov 22.
• [34] 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.
• [35] 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.
• [36] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [37] 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.
• [38] 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.
• [39] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [40] 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.
• [41] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [42] Epigenetic silencing of the candidate tumor suppressor gene PROX1 in sporadic breast cancer. Int J Cancer. 2007 Aug 1;121(3):547-54. doi: 10.1002/ijc.22705.
• [43] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [44] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [45] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [46] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [47] 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.
• [48] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [49] 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.
• [50] 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.
• [51] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [52] 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.
• [53] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [54] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.