title: Effects of thailanstatins on glucocorticoid response in trabecular meshwork and steroid-induced glaucoma.
abstract: OBJECTIVE
  Elevated intraocular pressure (IOP) is a major risk factor in glaucoma. Various changes in the trabecular meshwork (TM) are responsible for elevated IOP. Glucocorticoids (GCs) increase IOP and mediate biochemical changes in the TM, similar to those associated with primary open-angle glaucoma (POAG). There are differences in steroid responsiveness among the population. Approximately 40% of individuals significantly elevate IOP (i.e., responders) upon GC administration, while others do not (i.e., nonresponders). The responders are at higher risk of developing POAG compared to the nonresponders. In addition, almost all POAG patients are steroid responders. GC responsiveness is regulated by the relative levels of the active GC receptor alpha (GRα) and the alternatively spliced dominant negative regulator isoform GRβ. Glaucomatous TM cell strains have a lower GRβ-GRα ratio compared to normal TM cells, making them more sensitive to GCs. Our purpose was to investigate the role of a special class of natural products called thailanstatins (TSTs) in GR alternative splicing and GC response in cultured human TM cells.
  
  
  METHODS
  Quantitative RT-PCR and Western immunoblotting were used to study the effect of TSTs on GRβ-GRα ratios in human TM cell strains. Effects of TSTs on dexamethasone (DEX) responsiveness were assessed by GRE-luciferase reporter activity assay and fibronectin (FN) induction in TM cells.
  
  
  RESULTS
  TSTs increased the GRβ-GRα ratio in TM cells. Increased GRβ-GRα ratios were associated with decreased DEX-mediated FN induction and GRE-luciferase activity.
  
  
  CONCLUSIONS
  TSTs modulate the GR splicing process to enhance GRβ levels and thereby decrease the GC response in cultured human TM cells. These TSTs, or similar compounds, may potentially be new glaucoma therapeutic agents.
authors.affiliation: North Texas Eye Research Institute, Fort Worth, Texas 76107, USA.
authors.forename: Ankur
authors.initials: A
authors.lastname: Jain
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Liu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wordinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Yorio
authors.forename: Yi-Qiang
authors.initials: YQ
authors.lastname: Cheng
authors.forename: Abbot F
authors.initials: AF
authors.lastname: Clark
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers; D003907:Dexamethasone / Q000633:toxicity*; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D005901:Glaucoma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D005938:Glucocorticoids / Q000633:toxicity*; D006801:Humans; D011714:Pyrans / Q000494:pharmacology*; D012313:RNA / Q000302:isolation & purification; D012326:RNA Splicing / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017381:Spliceosomes / Q000187:drug effects; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D005353:Fibronectins; D005938:Glucocorticoids; D011714:Pyrans; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; C582010:thailanstatin A; C582011:thailanstatin B; C582012:thailanstatin C; D012313:RNA; D003907:Dexamethasone
keywords: glaucoma; glucocorticoid receptor; splicing; thailanstatins; trabecular meshwork
references.citation: Invest Ophthalmol Vis Sci. 1992 Jun;33(7):2242-50
references.pmid: 1607235
references.citation: J Med Chem. 2008 Oct 9;51(19):6220-4
references.pmid: 18788726
references.citation: J Rheumatol. 2001 Nov;28(11):2383-8
references.pmid: 11708406
references.citation: J Glaucoma. 1995 Oct;4(5):354-69
references.pmid: 19920699
references.citation: Zhonghua Nei Ke Za Zhi. 2001 Nov;40(11):725-8
references.pmid: 11930674
references.citation: Exp Eye Res. 2009 Apr;88(4):752-9
references.pmid: 18977348
references.citation: Nat Chem Biol. 2007 Sep;3(9):570-5
references.pmid: 17643112
references.citation: J Allergy Clin Immunol. 2001 Jul;108(1):59-68
references.pmid: 11447383
references.citation: J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):457-67
references.pmid: 12943736
references.citation: Curr Eye Res. 1993 Sep;12(9):783-93
references.pmid: 8261790
references.citation: Zhonghua Nei Ke Za Zhi. 2005 May;44(5):363-5
references.pmid: 16009008
references.citation: J Biol Chem. 1996 Apr 19;271(16):9550-9
references.pmid: 8621628
references.citation: Surv Ophthalmol. 1996 Mar-Apr;40(5):379-90
references.pmid: 8779084
references.citation: Horm Metab Res. 2000 Oct;32(10):401-6
references.pmid: 11069204
references.citation: Fed Proc. 1965 Nov-Dec;24(6):1274-8
references.pmid: 5853148
references.citation: J Nat Prod. 2013 Apr 26;76(4):685-93
references.pmid: 23517093
references.citation: J Antibiot (Tokyo). 2004 Mar;57(3):188-96
references.pmid: 15152804
references.citation: J Med Chem. 2009 Nov 26;52(22):6979-90
references.pmid: 19877647
references.citation: J Am Chem Soc. 2007 Mar 7;129(9):2648-59
references.pmid: 17279752
references.citation: Prog Retin Eye Res. 1999 Sep;18(5):629-67
references.pmid: 10438153
references.citation: Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1255-63
references.pmid: 18952927
references.citation: Invest Ophthalmol Vis Sci. 1998 Aug;39(9):1575-89
references.pmid: 9699547
references.citation: J Antibiot (Tokyo). 1996 Dec;49(12):1204-11
references.pmid: 9031665
references.citation: Zhonghua Yan Ke Za Zhi. 2006 May;42(5):431-4
references.pmid: 16762238
references.citation: Invest Ophthalmol Vis Sci. 2012 Feb 21;53(2):857-66
references.pmid: 22205602
references.citation: Curr Eye Res. 1994 Jan;13(1):51-63
references.pmid: 8156826
references.citation: Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1600-4
references.pmid: 10228133
references.citation: Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4607-16
references.pmid: 16303956
references.citation: Cell Motil Cytoskeleton. 2005 Feb;60(2):83-95
references.pmid: 15593281
references.citation: Invest Ophthalmol Vis Sci. 1994 Jan;35(1):281-94
references.pmid: 8300356
references.citation: Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1191-200
references.pmid: 17325163
references.citation: Nat Chem Biol. 2007 Sep;3(9):576-83
references.pmid: 17643111
references.citation: Mol Vis. 2010 Apr 03;16:596-601
references.pmid: 20376328
references.citation: Am J Ophthalmol. 1988 Nov 15;106(5):607-12
references.pmid: 3189477
references.citation: Gastroenterology. 2000 May;118(5):859-66
references.pmid: 10784585