Effects of thailanstatins on glucocorticoid response in trabecular meshwork and steroid-induced glaucoma

Ankur Jain, Xiangyang Liu, Robert J. Wordinger, Thomas Yorio, Yiqiang Cheng, Abbot Clark

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

PURPOSE. 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 (GRa) and the alternatively spliced dominant negative regulator isoform GRb. Glaucomatous TM cell strains have a lower GRb-GRa 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 GRb-GRa 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 GRb-GRa ratio in TM cells. Increased GRb-GRa ratios were associated with decreased DEX-mediated FN induction and GRE-luciferase activity. CONCLUSIONS. TSTs modulate the GR splicing process to enhance GRb levels and thereby decrease the GC response in cultured human TM cells. These TSTs, or similar compounds, may potentially be new glaucoma therapeutic agents.

Original languageEnglish
Pages (from-to)3137-3142
Number of pages6
JournalInvestigative Ophthalmology and Visual Science
Volume54
Issue number5
DOIs
StatePublished - 10 May 2013

Fingerprint

Trabecular Meshwork
Glaucoma
Glucocorticoids
Steroids
Intraocular Pressure
Luciferases
Fibronectins
Dexamethasone
Alternative Splicing
Biological Products
Protein Isoforms
Western Blotting
Polymerase Chain Reaction

Keywords

  • Glaucoma
  • Glucocorticoid receptor
  • Splicing
  • Thailanstatins
  • Trabecular meshwork

Cite this

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title = "Effects of thailanstatins on glucocorticoid response in trabecular meshwork and steroid-induced glaucoma",
abstract = "PURPOSE. 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 (GRa) and the alternatively spliced dominant negative regulator isoform GRb. Glaucomatous TM cell strains have a lower GRb-GRa 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 GRb-GRa 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 GRb-GRa ratio in TM cells. Increased GRb-GRa ratios were associated with decreased DEX-mediated FN induction and GRE-luciferase activity. CONCLUSIONS. TSTs modulate the GR splicing process to enhance GRb levels and thereby decrease the GC response in cultured human TM cells. These TSTs, or similar compounds, may potentially be new glaucoma therapeutic agents.",
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author = "Ankur Jain and Xiangyang Liu and Wordinger, {Robert J.} and Thomas Yorio and Yiqiang Cheng and Abbot Clark",
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Effects of thailanstatins on glucocorticoid response in trabecular meshwork and steroid-induced glaucoma. / Jain, Ankur; Liu, Xiangyang; Wordinger, Robert J.; Yorio, Thomas; Cheng, Yiqiang; Clark, Abbot.

In: Investigative Ophthalmology and Visual Science, Vol. 54, No. 5, 10.05.2013, p. 3137-3142.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effects of thailanstatins on glucocorticoid response in trabecular meshwork and steroid-induced glaucoma

AU - Jain, Ankur

AU - Liu, Xiangyang

AU - Wordinger, Robert J.

AU - Yorio, Thomas

AU - Cheng, Yiqiang

AU - Clark, Abbot

PY - 2013/5/10

Y1 - 2013/5/10

N2 - PURPOSE. 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 (GRa) and the alternatively spliced dominant negative regulator isoform GRb. Glaucomatous TM cell strains have a lower GRb-GRa 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 GRb-GRa 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 GRb-GRa ratio in TM cells. Increased GRb-GRa ratios were associated with decreased DEX-mediated FN induction and GRE-luciferase activity. CONCLUSIONS. TSTs modulate the GR splicing process to enhance GRb levels and thereby decrease the GC response in cultured human TM cells. These TSTs, or similar compounds, may potentially be new glaucoma therapeutic agents.

AB - PURPOSE. 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 (GRa) and the alternatively spliced dominant negative regulator isoform GRb. Glaucomatous TM cell strains have a lower GRb-GRa 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 GRb-GRa 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 GRb-GRa ratio in TM cells. Increased GRb-GRa ratios were associated with decreased DEX-mediated FN induction and GRE-luciferase activity. CONCLUSIONS. TSTs modulate the GR splicing process to enhance GRb levels and thereby decrease the GC response in cultured human TM cells. These TSTs, or similar compounds, may potentially be new glaucoma therapeutic agents.

KW - Glaucoma

KW - Glucocorticoid receptor

KW - Splicing

KW - Thailanstatins

KW - Trabecular meshwork

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DO - 10.1167/iovs.12-11480

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JO - Investigative Ophthalmology and Visual Science

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