Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGW2974)

• DOT Name: Protein prune homolog 2 (PRUNE2)
• Synonyms: BNIP2 motif-containing molecule at the C-terminal region 1
• Gene Name: PRUNE2
• Related Disease:
  Advanced cancer
  Cerebellar ataxia
  Dental caries
  Immunodeficiency
  Metastatic malignant neoplasm
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Adult glioblastoma
  Alzheimer disease
  Gastrointestinal stromal tumour
  Glioblastoma multiforme
  Leiomyosarcoma
  Neuroblastoma
  Parathyroid gland carcinoma
• UniProt ID: PRUN2_HUMAN
• Pfam ID: PF12496 ; PF13716 ; PF02833
• Sequence:
  MEEFLQRAKSKLNRSKRLEKVHVVIGPKSCDLDSLISTFTYAYFLDKVSPPGVLCLPVLN
  IPRTEFNYFTETRFILEELNISESFHIFRDEINLHQLNDEGKLSITLVGSSVLASEDKTL
  ESAVVKVINPVEQSDANVEFRESSSSLVLKEILQEAPELITEQLAHRLRGSILFKWMTME
  SEKISEKQEEILSILEEKFPNLPPREDIINVLQETQFSAQGLSIEQTMLKDLKELSDGEI
  KVAISTVSMNLENCLFHSNITSDLKAFTDKFGFDVLILFSSYLSEEQQPRRQIAVYSENM
  ELCSQICCELEECQNPCLELEPFDCGCDEILVYQQEDPSVTCDQVVLVVKEVINRRCPEM
  VSNSRTSSTEAVAGSAPLSQGSSGIMELYGSDIEPQPSSVNFIENPPDLNDSNQAQVDAN
  VDLVSPDSGLATIRSSRSSKESSVFLSDDSPVGEGAGPHHTLLPGLDSYSPIPEGAVAEE
  HAWSGEHGEHFDLFNFDPAPMASGQSQQSSHSADYSPADDFFPNSDLSEGQLPAGPEGLD
  GMGTNMSNYSSSSLLSGAGKDSLVEHDEEFVQRQDSPRDNSERNLSLTDFVGDESPSPER
  LKNTGKRIPPTPMNSLVESSPSTEEPASLYTEDMTQKATDTGHMGPPQTHARCSSWWGGL
  EIDSKNIADAWSSSEQESVFQSPESWKEHKPSSIDRRASDSVFQPKSLEFTKSGPWESEF
  GQPELGSNDIQDKNEESLPFQNLPMEKSPLPNTSPQGTNHLIEDFASLWHSGRSPTAMPE
  PWGNPTDDGEPAAVAPFPAWSAFGKEDHDEALKNTWNLHPTSSKTPSVRDPNEWAMAKSG
  FAFSSSELLDNSPSEINNEAAPEIWGKKNNDSRDHIFAPGNPSSDLDHTWTNSKPPKEDQ
  NGLVDPKTRGKVYEKVDSWNLFEENMKKGGSDVLVPWEDSFLSYKCSDYSASNLGEDSVP
  SPLDTNYSTSDSYTSPTFAGDEKETEHKPFAKEEGFESKDGNSTAEETDIPPQSLQQSSR
  NRISSGPGNLDMWASPHTDNSSEINTTHNLDENELKTEHTDGKNISMEDDVGESSQSSYD
  DPSMMQLYNETNRQLTLLHSSTNSRQTAPDSLDLWNRVILEDTQSTATISDMDNDLDWDD
  CSGGAAIPSDGQTEGYMAEGSEPETRFTVRQLEPWGLEYQEANQVDWELPASDEHTKDSA
  PSEHHTLNEKSGQLIANSIWDSVMRDKDMSSFMLPGSSHITDSEQRELPPEIPSHSANVK
  DTHSPDAPAASGTSESEALISHLDKQDTERETLQSDAASLATRLENPGYFPHPDPWKGHG
  DGQSESEKEAQGATDRGHLDEEEVIASGVENASGISEKGQSDQELSSLVASEHQEICIKS
  GKISSLAVTFSPQTEEPEEVLEYEEGSYNLDSRDVQTGMSADNLQPKDTHEKHLMSQRNS
  GETTETSDGMNFTKYVSVPEKDLEKTEECNFLEPENVGGGPPHRVPRSLDFGDVPIDSDV
  HVSSTCSEITKNLDVKGSENSLPGAGSSGNFDRDTISSEYTHSSASSPELNDSSVALSSW
  GQQPSSGYQEENQGNWSEQNHQESELITTDGQVEIVTKVKDLEKNRINEFEKSFDRKTPT
  FLEIWNDSVDGDSFSSLSSPETGKYSEHSGTHQESNLIASYQEKNEHDISATVQPEDARV
  ISTSSGSDDDSVGGEESIEEEIQVANCHVAEDESRAWDSLNESNKFLVTADPKSENIYDY
  LDSSEPAENENKSNPFCDNQQSSPDPWTFSPLTETEMQITAVEKEKRSSPETGTTGDVAW
  QISPKASFPKNEDNSQLEMLGFSADSTEWWKASPQEGRLIESPFERELSDSSGVLEINSS
  VHQNASPWGVPVQGDIEPVETHYTNPFSDNHQSPFLEGNGKNSHEQLWNIQPRQPDPDAD
  KFSQLVKLDQIKEKDSREQTFVSAAGDELTPETPTQEQCQDTMLPVCDHPDTAFTHAEEN
  SCVTSNVSTNEGQETNQWEQEKSYLGEMTNSSIATENFPAVSSPTQLIMKPGSEWDGSTP
  SEDSRGTFVPDILHGNFQEGGQLASAAPDLWIDAKKPFSLKADGENPDILTHCEHDSNSQ
  ASDSPDICHDSEAKQETEKHLSACMGPEVESSELCLTEPEIDEEPIYEPGREFVPSNAEL
  DSENATVLPPIGYQADIKGSSQPASHKGSPEPSEINGDNSTGLQVSEKGASPDMAPILEP
  VDRRIPRIENVATSIFVTHQEPTPEGDGSWISDSFSPESQPGARALFDGDPHLSTENPAL
  VPDALLASDTCLDISEAAFDHSFSDASGLNTSTGTIDDMSKLTLSEGHPETPVDGDLGKQ
  DICSSEASWGDFEYDVMGQNIDEDLLREPEHFLYGGDPPLEEDSLKQSLAPYTPPFDLSY
  LTEPAQSAETIEEAGSPEDESLGCRAAEIVLSALPDRRSEGNQAETKNRLPGSQLAVLHI
  REDPESVYLPVGAGSNILSPSNVDWEVETDNSDLPAGGDIGPPNGASKEISELEEEKTIP
  TKEPEQIKSEYKEERCTEKNEDRHALHMDYILVNREENSHSKPETCEERESIAELELYVG
  SKETGLQGTQLASFPDTCQPASLNERKGLSAEKMSSKSDTRSSFESPAQDQSWMFLGHSE
  VGDPSLDARDSGPGWSGKTVEPFSELGLGEGPQLQILEEMKPLESLALEEASGPVSQSQK
  SKSRGRAGPDAVTLQAVTHDNEWEMLSPQPVQKNMIPDTEMEEETEFLELGTRISRPNGL
  LSEDVGMDIPFEEGVLSPSAADMRPEPPNSLDLNDTHPRRIKLTAPNINLSLDQSEGSIL
  SDDNLDSPDEIDINVDELDTPDEADSFEYTGHDPTANKDSGQESESIPEYTAEEEREDNR
  LWRTVVIGEQEQRIDMKVIEPYRRVISHGGYYGDGLNAIIVFAACFLPDSSRADYHYVME
  NLFLYVISTLELMVAEDYMIVYLNGATPRRRMPGLGWMKKCYQMIDRRLRKNLKSFIIVH
  PSWFIRTILAVTRPFISSKFSSKIKYVNSLSELSGLIPMDCIHIPESIIKLDEELREASE
  AAKTSCLYNDPEMSSMEKDIDLKLKEKP
• Function: May play an important role in regulating differentiation, survival and aggressiveness of the tumor cells.
• Tissue Specificity: A high level of expression seen in the nervous system (brain, cerebellum and spinal cord) as well as adrenal gland. Expressed at high levels in noneuroblastoma, rhabdomyosarcoma, melanoma and some osteosarcoma cell lines, whereas at only low levels in cancer cell lines of liver, breast, thyroid and colon. Expression is significantly higher in favorable tumors than aggressive ones.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[2]
Dental caries	DISRBCMD	Strong	Genetic Variation	[3]
Immunodeficiency	DIS093I0	Strong	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[7]
Alzheimer disease	DISF8S70	Limited	Biomarker	[8]
Gastrointestinal stromal tumour	DIS6TJYS	Limited	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[7]
Leiomyosarcoma	DIS6COXM	Limited	Biomarker	[8]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[6]
Parathyroid gland carcinoma	DISEER2W	Limited	Genetic Variation	[10]

23 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 Protein prune homolog 2 (PRUNE2).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein prune homolog 2 (PRUNE2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein prune homolog 2 (PRUNE2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein prune homolog 2 (PRUNE2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Protein prune homolog 2 (PRUNE2).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein prune homolog 2 (PRUNE2).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein prune homolog 2 (PRUNE2).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein prune homolog 2 (PRUNE2).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protein prune homolog 2 (PRUNE2).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein prune homolog 2 (PRUNE2).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Protein prune homolog 2 (PRUNE2).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Protein prune homolog 2 (PRUNE2).	[22]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Protein prune homolog 2 (PRUNE2).	[23]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Protein prune homolog 2 (PRUNE2).	[24]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Protein prune homolog 2 (PRUNE2).	[25]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Protein prune homolog 2 (PRUNE2).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein prune homolog 2 (PRUNE2).	[21]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Protein prune homolog 2 (PRUNE2).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein prune homolog 2 (PRUNE2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein prune homolog 2 (PRUNE2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein prune homolog 2 (PRUNE2).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein prune homolog 2 (PRUNE2).	[30]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Protein prune homolog 2 (PRUNE2).	[31]

References

• [1] Cancer-related PRUNE2 protein is associated with nucleotides and is highly expressed in mature nerve tissues.J Mol Neurosci. 2011 Jun;44(2):103-14. doi: 10.1007/s12031-010-9490-2. Epub 2011 Jan 14.
• [2] Odor preference and olfactory memory are impaired in Olfaxin-deficient mice.Brain Res. 2018 Jun 1;1688:81-90. doi: 10.1016/j.brainres.2018.03.025. Epub 2018 Mar 20.
• [3] Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.Nat Commun. 2019 Jun 24;10(1):2773. doi: 10.1038/s41467-019-10630-1.
• [4] PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3.Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8403-8. doi: 10.1073/pnas.1507882112. Epub 2015 Jun 15.
• [5] New genomic structure for prostate cancer specific gene PCA3 within BMCC1: implications for prostate cancer detection and progression.PLoS One. 2009;4(3):e4995. doi: 10.1371/journal.pone.0004995. Epub 2009 Mar 25.
• [6] Programmed expression of pro-apoptotic BMCC1 during apoptosis, triggered by DNA damage in neuroblastoma cells.BMC Cancer. 2019 Jun 6;19(1):542. doi: 10.1186/s12885-019-5772-4.
• [7] KLRC3, a Natural Killer receptor gene, is a key factor involved in glioblastoma tumourigenesis and aggressiveness.J Cell Mol Med. 2017 Feb;21(2):244-253. doi: 10.1111/jcmm.12960. Epub 2016 Sep 19.
• [8] Expression patterns of prune2 is regulated by Notch and retinoic acid signaling pathways in the zebrafish embryogenesis.Gene Expr Patterns. 2017 Jan;23-24:45-51. doi: 10.1016/j.gep.2017.03.002. Epub 2017 Mar 11.
• [9] Highly accurate two-gene classifier for differentiating gastrointestinal stromal tumors and leiomyosarcomas.Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3414-9. doi: 10.1073/pnas.0611373104. Epub 2007 Feb 21.
• [10] Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion.J Clin Endocrinol Metab. 2015 Feb;100(2):E360-4. doi: 10.1210/jc.2014-3238. Epub 2014 Nov 11.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] 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.
• [16] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] 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.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] 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.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] 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.
• [24] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [25] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [26] Ultradian cortisol pulsatility encodes a distinct, biologically important signal. PLoS One. 2011 Jan 18;6(1):e15766.
• [27] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [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] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [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] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.