PRMT5 is a therapeutic target in choroidal neovascularization.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
31 01 2023
31 01 2023
Historique:
received:
15
07
2022
accepted:
16
01
2023
entrez:
31
1
2023
pubmed:
1
2
2023
medline:
3
2
2023
Statut:
epublish
Résumé
Ocular neovascular diseases including neovascular age-related macular degeneration (nvAMD) are widespread causes of blindness. Patients' non-responsiveness to currently used biologics that target vascular endothelial growth factor (VEGF) poses an unmet need for novel therapies. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a novel therapeutic target for nvAMD. PRMT5 is a well-known epigenetic enzyme. We previously showed that PRMT5 methylates and activates a proangiogenic and proinflammatory transcription factor, the nuclear factor kappa B (NF-κB), which has a master role in tumor progression, notably in pancreatic ductal adenocarcinoma and colorectal cancer. We identified a potent and specific small molecule inhibitor of PRMT5, PR5-LL-CM01, that dampens the methylation and activation of NF-κB. Here for the first time, we assessed the antiangiogenic activity of PR5-LL-CM01 in ocular cells. Immunostaining of human nvAMD sections revealed that PRMT5 is highly expressed in the retinal pigment epithelium (RPE)/choroid where neovascularization occurs, while mouse eyes with laser induced choroidal neovascularization (L-CNV) showed PRMT5 is overexpressed in the retinal ganglion cell layer and in the RPE/choroid. Importantly, inhibition of PRMT5 by PR5-LL-CM01 or shRNA knockdown of PRMT5 in human retinal endothelial cells (HRECs) and induced pluripotent stem cell (iPSC)-derived choroidal endothelial cells (iCEC2) reduced NF-κB activity and the expression of its target genes, such as tumor necrosis factor α (TNF-α) and VEGF-A. In addition to inhibiting angiogenic properties of proliferation and tube formation, PR5-LL-CM01 blocked cell cycle progression at G
Identifiants
pubmed: 36720900
doi: 10.1038/s41598-023-28215-w
pii: 10.1038/s41598-023-28215-w
pmc: PMC9889383
doi:
Substances chimiques
Vascular Endothelial Growth Factor A
0
PR5-LL-CM01
0
NF-kappa B
0
PRMT5 protein, human
EC 2.1.1.319
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1747Subventions
Organisme : NCATS NIH HHS
ID : UL1TR002529
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002529
Pays : United States
Organisme : NEI NIH HHS
ID : R01EY025641
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY025641
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY031939
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Cancer Res. 1999 Sep 1;59(17):4446-52
pubmed: 10485496
Exp Eye Res. 2014 Oct;127:49-58
pubmed: 25041941
J Neurosci. 1995 Jul;15(7 Pt 1):4738-47
pubmed: 7623107
Ocul Surf. 2012 Jul;10(3):137-48
pubmed: 22814642
Cell Cycle. 2014;13(1):32-41
pubmed: 24296620
Oncol Rep. 2010 Mar;23(3):725-32
pubmed: 20127012
J Pharmacol Exp Ther. 2018 Oct;367(1):108-118
pubmed: 30076264
EMBO Mol Med. 2017 Jun;9(6):786-801
pubmed: 28377496
Nat Protoc. 2013 Nov;8(11):2197-211
pubmed: 24136346
J Med Chem. 2018 Nov 8;61(21):9429-9441
pubmed: 29870258
Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2832-7
pubmed: 8610127
Nat Commun. 2021 Dec 15;12(1):7293
pubmed: 34911940
Oncogene. 1999 May 27;18(21):3213-25
pubmed: 10359527
Cancer Res. 2015 Sep 15;75(18):3692-5
pubmed: 26337909
Am J Pathol. 2021 May;191(5):947-964
pubmed: 33640319
Cancer Sci. 2012 Sep;103(9):1640-50
pubmed: 22726390
Am J Pathol. 2015 Dec;185(12):3316-25
pubmed: 26476350
J Neurooncol. 2014 May;118(1):61-72
pubmed: 24664369
J Pathol. 2017 Apr;241(5):583-588
pubmed: 28026019
J Med Chem. 2015 Jun 25;58(12):5015-5027
pubmed: 26035340
Eur J Pharmacol. 2016 Sep 15;787:84-93
pubmed: 27044435
Int J Mol Sci. 2021 Jul 11;22(14):
pubmed: 34299049
Oncogene. 2017 Mar 2;36(9):1223-1231
pubmed: 27546619
Sci Rep. 2016 Jul 11;6:29619
pubmed: 27403807
Cell Commun Signal. 2019 Mar 29;17(1):30
pubmed: 30922330
Cancer Med. 2018 Mar;7(3):869-882
pubmed: 29441724
Exp Eye Res. 2006 Dec;83(6):1325-34
pubmed: 16959248
Mol Vis. 2016 Feb 03;22:116-28
pubmed: 26900328
Redox Biol. 2014 Feb 21;2:485-94
pubmed: 24624338
Arch Ophthalmol. 2004 Jul;122(7):1013-8
pubmed: 15249366
Am J Pathol. 2001 Aug;159(2):387-97
pubmed: 11485895
J Cell Sci. 2009 Mar 1;122(Pt 5):667-77
pubmed: 19208762
Invest Ophthalmol Vis Sci. 2014 Jul 01;55(8):4944-51
pubmed: 24985472
Cell Res. 2011 Jan;21(1):71-85
pubmed: 21173796
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13516-21
pubmed: 23904475
Mol Biosyst. 2017 Nov 21;13(12):2509-2520
pubmed: 29099132
Prog Retin Eye Res. 2021 Sep;84:100954
pubmed: 33640465
Mol Vis. 2016 Feb 27;22:189-202
pubmed: 27013848
Invest Ophthalmol Vis Sci. 2001 Mar;42(3):795-803
pubmed: 11222543
Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2555-62
pubmed: 17932319
J Pathol. 2016 Feb;238(3):446-56
pubmed: 26564985
Cell Rep. 2020 Jun 23;31(12):107776
pubmed: 32579912
Theranostics. 2021 Aug 28;11(18):9162-9176
pubmed: 34522232
J Cell Physiol. 2012 Jan;227(1):116-26
pubmed: 21374591
Invest Ophthalmol Vis Sci. 1999 Aug;40(9):1891-8
pubmed: 10440240
J Vis Exp. 2015 Dec 27;(106):e53502
pubmed: 26779879
Mediators Inflamm. 2014;2014:930671
pubmed: 25214719
Biomed Pharmacother. 2019 Jun;114:108790
pubmed: 30903920
Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24100-24107
pubmed: 31712411
Mol Cell Biol. 1997 Nov;17(11):6526-36
pubmed: 9343416
Exp Eye Res. 2003 Apr;76(4):463-71
pubmed: 12634111
Nucleic Acids Res. 2011 Jun;39(11):4719-27
pubmed: 21321020
Cell Transplant. 2019 Dec;28(12):1664-1673
pubmed: 31665911
Biomed Pharmacother. 2021 Jan;133:110999
pubmed: 33227710
Sci Rep. 2020 Sep 28;10(1):15934
pubmed: 32985589
Cell Rep. 2017 Dec 19;21(12):3498-3513
pubmed: 29262329
Exp Eye Res. 2021 Jan;202:108286
pubmed: 33035554
PLoS One. 2014 Jan 28;9(1):e87530
pubmed: 24489934
Mol Vis. 2015 May 01;21:515-22
pubmed: 25999678
Nat Cell Biol. 2008 Dec;10(12):1431-9
pubmed: 19011621
Invest Ophthalmol Vis Sci. 1996 Jun;37(7):1236-49
pubmed: 8641827
Ann Med. 2012 Feb;44(1):1-17
pubmed: 21284527
Genes Dis. 2019 Jun 19;6(3):247-257
pubmed: 32042864
Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5479-86
pubmed: 19494202
Oncotarget. 2017 Jun 20;8(25):39963-39977
pubmed: 28591716
Prog Retin Eye Res. 2015 Nov;49:67-81
pubmed: 26113211
Med Hypotheses. 2012 Apr;78(4):505-10
pubmed: 22296808
FASEB J. 2020 Sep;34(9):12419-12435
pubmed: 32716567
Exp Cell Res. 2021 Jun 1;403(1):112581
pubmed: 33811906
Nat Cell Biol. 2011 Feb;13(2):174-81
pubmed: 21258366
Curr Mol Med. 2001 Jul;1(3):287-96
pubmed: 11899077
FEBS J. 2005 Nov;272(22):5821-31
pubmed: 16279946
Aging (Albany NY). 2021 Jan 20;13(3):4468-4481
pubmed: 33495409
Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):337-342
pubmed: 30446222
Front Neurosci. 2018 Nov 15;12:834
pubmed: 30524222
Sci Rep. 2017 Aug 29;7(1):9672
pubmed: 28852052
PLoS One. 2010 Jul 29;5(7):e11863
pubmed: 20686684
PLoS One. 2021 Jun 8;16(6):e0251931
pubmed: 34101738
J Biol Chem. 2004 May 7;279(19):20221-33
pubmed: 14960579
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):46-51
pubmed: 20080798
Signal Transduct Target Ther. 2017;2:
pubmed: 29158945
Cell Stress. 2020 Jul 13;4(8):199-215
pubmed: 32743345
Adv Exp Med Biol. 2021;1256:1-31
pubmed: 33847996
Int J Mol Med. 2015 Jul;36(1):301-8
pubmed: 25955241