Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8UR4AU)

• DOT Name: Paired mesoderm homeobox protein 2 (PRRX2)
• Synonyms: Paired-related homeobox protein 2; PRX-2
• Gene Name: PRRX2
• Related Disease:
  Alzheimer disease
  Amyotrophic lateral sclerosis type 1
  Angiosarcoma
  Autism spectrum disorder
  Beta-thalassemia major
  Brain disease
  Colon cancer
  Colon carcinoma
  Familial amyotrophic lateral sclerosis
  Hepatocellular carcinoma
  Late-onset Parkinson disease
  Nager acrofacial dysostosis
  Non-small-cell lung cancer
  Parkinson disease
  Pick disease
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  Castration-resistant prostate carcinoma
  Prostate cancer
  Prostate carcinoma
  Subarachnoid hemorrhage
  Advanced cancer
  Gastric cancer
  Neoplasm
  Sickle-cell anaemia
  Stomach cancer
• UniProt ID: PRRX2_HUMAN
• Pfam ID: PF00046 ; PF03826
• Sequence:
  MDSAAAAFALDKPALGPGPPPPPPALGPGDCAQARKNFSVSHLLDLEEVAAAGRLAARPG
  ARAEAREGAAREPSGGSSGSEAAPQDGECPSPGRGSAAKRKKKQRRNRTTFNSSQLQALE
  RVFERTHYPDAFVREELARRVNLSEARVQVWFQNRRAKFRRNERAMLASRSASLLKSYSQ
  EAAIEQPVAPRPTALSPDYLSWTASSPYSTVPPYSPGSSGPATPGVNMANSIASLRLKAK
  EFSLHHSQVPTVN
• Function: May play a role in the scarless healing of cutaneous wounds during the first two trimesters of development.
• Tissue Specificity: In fetal skin, highest expression found in cells of mesodermal origin within the dermal papilla of the developing hair shaft. Not detected in epidermis or dermis. In adult skin, weakly expressed within the basal layers of the epidermis. Not expressed in dermis.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Genetic Variation	[2]
Angiosarcoma	DISIYS9W	Strong	Altered Expression	[3]
Autism spectrum disorder	DISXK8NV	Strong	Altered Expression	[4]
Beta-thalassemia major	DISW06BV	Strong	Biomarker	[5]
Brain disease	DIS6ZC3X	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[8]
Late-onset Parkinson disease	DIS9IOUI	Strong	Biomarker	[9]
Nager acrofacial dysostosis	DIS9WQOT	Strong	Genetic Variation	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[12]
Pick disease	DISP6X50	Strong	Altered Expression	[13]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[14]
Breast cancer	DIS7DPX1	moderate	Biomarker	[15]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[15]
Castration-resistant prostate carcinoma	DISVGAE6	moderate	Biomarker	[16]
Prostate cancer	DISF190Y	moderate	Biomarker	[16]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[16]
Subarachnoid hemorrhage	DISI7I8Y	Disputed	Biomarker	[17]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[18]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[19]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[7]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[20]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Paired mesoderm homeobox protein 2 (PRRX2) affects the response to substance of Temozolomide.	[31]
DTI-015	DMXZRW0	Approved	Paired mesoderm homeobox protein 2 (PRRX2) affects the response to substance of DTI-015.	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Paired mesoderm homeobox protein 2 (PRRX2).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Paired mesoderm homeobox protein 2 (PRRX2).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Paired mesoderm homeobox protein 2 (PRRX2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Paired mesoderm homeobox protein 2 (PRRX2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Paired mesoderm homeobox protein 2 (PRRX2).	[23]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Paired mesoderm homeobox protein 2 (PRRX2).	[24]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Paired mesoderm homeobox protein 2 (PRRX2).	[25]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Paired mesoderm homeobox protein 2 (PRRX2).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Paired mesoderm homeobox protein 2 (PRRX2).	[29]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Paired mesoderm homeobox protein 2 (PRRX2).	[30]

References

• [1] Increase in expression levels and resistance to sulfhydryl oxidation of peroxiredoxin isoforms in amyloid beta-resistant nerve cells.J Biol Chem. 2007 Oct 19;282(42):30523-34. doi: 10.1074/jbc.M700869200. Epub 2007 Aug 29.
• [2] Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models.Acta Neuropathol. 2004 Feb;107(2):149-58. doi: 10.1007/s00401-003-0791-1. Epub 2003 Nov 27.
• [3] Expression of peroxiredoxin II in vascular tumors of the skin: a novel vascular marker of endothelial cells.J Am Acad Dermatol. 2003 Sep;49(3):487-91. doi: 10.1067/s0190-9622(03)01485-3.
• [4] Plasma peroxiredoxin changes and inflammatory cytokines support the involvement of neuro-inflammation and oxidative stress in Autism Spectrum Disorder.J Transl Med. 2019 Oct 2;17(1):332. doi: 10.1186/s12967-019-2076-z.
• [5] Global analysis of erythroid cells redox status reveals the involvement of Prdx1 and Prdx2 in the severity of beta thalassemia.PLoS One. 2018 Dec 6;13(12):e0208316. doi: 10.1371/journal.pone.0208316. eCollection 2018.
• [6] Neuroprotective effect of PEP-1-peroxiredoxin2 on CA1 regions in the hippocampus against ischemic insult.Biochim Biophys Acta. 2014 Jul;1840(7):2321-30. doi: 10.1016/j.bbagen.2014.03.003. Epub 2014 Mar 12.
• [7] Inhibition of PRRX2 suppressed colon cancer liver metastasis via inactivation of Wnt/-catenin signaling pathway.Pathol Res Pract. 2019 Oct;215(10):152593. doi: 10.1016/j.prp.2019.152593. Epub 2019 Aug 11.
• [8] Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway.Oncogene. 2016 Jul 7;35(27):3503-13. doi: 10.1038/onc.2015.411. Epub 2015 Oct 26.
• [9] Peroxiredoxin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade.J Neurosci. 2011 Jan 5;31(1):247-61. doi: 10.1523/JNEUROSCI.4589-10.2011.
• [10] Human PRRX1 and PRRX2 genes: cloning, expression, genomic localization, and exclusion as disease genes for Nager syndrome.Mamm Genome. 2000 Nov;11(11):1000-5. doi: 10.1007/s003350010193.
• [11] MicroRNA-122 negatively associates with peroxiredoxin-II expression in human gefitinib-resistant lung cancer stem cells.Cancer Gene Ther. 2019 Sep;26(9-10):292-304. doi: 10.1038/s41417-018-0050-1. Epub 2018 Oct 19.
• [12] Inhibition of HDAC6 increases acetylation of peroxiredoxin1/2 and ameliorates 6-OHDA induced dopaminergic injury.Neurosci Lett. 2017 Sep 29;658:114-120. doi: 10.1016/j.neulet.2017.08.029. Epub 2017 Aug 18.
• [13] Aberrant expression of peroxiredoxin subtypes in neurodegenerative disorders.Brain Res. 2003 Mar 28;967(1-2):152-60. doi: 10.1016/s0006-8993(02)04243-9.
• [14] MiR-212-5p Suppresses the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer by Targeting Prrx2.Cell Physiol Biochem. 2017;44(5):1785-1795. doi: 10.1159/000485785. Epub 2017 Dec 6.
• [15] Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition.Cell Physiol Biochem. 2017;42(5):1847-1856. doi: 10.1159/000479542. Epub 2017 Jul 27.
• [16] Peroxiredoxin 2 in the nucleus and cytoplasm distinctly regulates androgen receptor activity in prostate cancer cells.Free Radic Biol Med. 2011 Jul 1;51(1):78-87. doi: 10.1016/j.freeradbiomed.2011.04.001. Epub 2011 Apr 14.
• [17] Peroxiredoxin 2 activates microglia by interacting with Toll-like receptor 4 after subarachnoid hemorrhage.J Neuroinflammation. 2018 Mar 19;15(1):87. doi: 10.1186/s12974-018-1118-4.
• [18] Prx2 links ROS homeostasis to stemness of cancer stem cells.Free Radic Biol Med. 2019 Apr;134:260-267. doi: 10.1016/j.freeradbiomed.2019.01.001. Epub 2019 Jan 4.
• [19] Downregulation of peroxiredoxin II suppresses the proliferation and metastasis of gastric cancer cells.Oncol Lett. 2018 Oct;16(4):4551-4560. doi: 10.3892/ol.2018.9208. Epub 2018 Jul 25.
• [20] Erythrocyte and plasma oxidative stress appears to be compensated in patients with sickle cell disease during a period of relative health, despite the presence of known oxidative agents.Free Radic Biol Med. 2019 Sep;141:408-415. doi: 10.1016/j.freeradbiomed.2019.07.004. Epub 2019 Jul 3.
• [21] 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.
• [22] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [23] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [24] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [25] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [26] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [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] 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.
• [29] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [30] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [31] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.