Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.

Withaferin A (WFA) is a natural product that binds to soluble forms of the type III intermediate filament (IF) vimentin. Currently, it is unknown under what pathophysiological contexts vimentin is druggable, as cytoskeltal vimentin-IFs are abundantly expressed. To investigate druggability of vimenti...

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Autores principales:	Paola Bargagna-Mohan, Sunil P Deokule, Kyle Thompson, John Wizeman, Cidambi Srinivasan, Sunil Vooturi, Uday B Kompella, Royce Mohan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9d42ba520c0441daa78792964c03f0a7
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spelling	oai:doaj.org-article:9d42ba520c0441daa78792964c03f0a72021-11-18T07:46:17ZWithaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.1932-620310.1371/journal.pone.0063881https://doaj.org/article/9d42ba520c0441daa78792964c03f0a72013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23667686/?tool=EBIhttps://doaj.org/toc/1932-6203Withaferin A (WFA) is a natural product that binds to soluble forms of the type III intermediate filament (IF) vimentin. Currently, it is unknown under what pathophysiological contexts vimentin is druggable, as cytoskeltal vimentin-IFs are abundantly expressed. To investigate druggability of vimentin, we exploited rabbit Tenon's capsule fibroblast (RbTCF) cell cultures and the rabbit glaucoma filtration surgical (GFS) model of fibrosis. WFA potently caused G₀/G₁ cell cycle inhibition (IC₅₀ 25 nM) in RbTCFs, downregulating ubiquitin E3 ligase skp2 and inducing p27(Kip1) expression. Transforming growth factor (TGF)-ß-induced myofibroblast transformation caused development of cell spheroids with numerous elongated invadopodia, which WFA blocked potently by downregulating soluble vimentin and α-smooth muscle actin (SMA) expression. In the pilot proof-of-concept study using the GFS model, subconjunctival injections of a low WFA dose reduced skp2 expression in Tenon's capsule and increased p27(Kip1) expression without significant alteration to vimentin-IFs. This treatment maintains significant nanomolar WFA concentrations in anterior segment tissues that correspond to WFA's cell cycle targeting activity. A ten-fold higher WFA dose caused potent downregulation of soluble vimentin and skp2 expression, but as found in cell cultures, no further increase in p27(Kip1) expression was observed. Instead, this high WFA dose potently induced vimentin-IF disruption and downregulated α-SMA expression that mimicked WFA activity in TGF-ß-treated RbTCFs that blocked cell contractile activity at submicromolar concentrations. These findings illuminate that localized WFA injection to ocular tissues exerts pharmacological control over the skp2-p27(Kip1) pathway by targeting of soluble vimentin in a model of surgical fibrosis.Paola Bargagna-MohanSunil P DeokuleKyle ThompsonJohn WizemanCidambi SrinivasanSunil VooturiUday B KompellaRoyce MohanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e63881 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paola Bargagna-Mohan Sunil P Deokule Kyle Thompson John Wizeman Cidambi Srinivasan Sunil Vooturi Uday B Kompella Royce Mohan Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.
description	Withaferin A (WFA) is a natural product that binds to soluble forms of the type III intermediate filament (IF) vimentin. Currently, it is unknown under what pathophysiological contexts vimentin is druggable, as cytoskeltal vimentin-IFs are abundantly expressed. To investigate druggability of vimentin, we exploited rabbit Tenon's capsule fibroblast (RbTCF) cell cultures and the rabbit glaucoma filtration surgical (GFS) model of fibrosis. WFA potently caused G₀/G₁ cell cycle inhibition (IC₅₀ 25 nM) in RbTCFs, downregulating ubiquitin E3 ligase skp2 and inducing p27(Kip1) expression. Transforming growth factor (TGF)-ß-induced myofibroblast transformation caused development of cell spheroids with numerous elongated invadopodia, which WFA blocked potently by downregulating soluble vimentin and α-smooth muscle actin (SMA) expression. In the pilot proof-of-concept study using the GFS model, subconjunctival injections of a low WFA dose reduced skp2 expression in Tenon's capsule and increased p27(Kip1) expression without significant alteration to vimentin-IFs. This treatment maintains significant nanomolar WFA concentrations in anterior segment tissues that correspond to WFA's cell cycle targeting activity. A ten-fold higher WFA dose caused potent downregulation of soluble vimentin and skp2 expression, but as found in cell cultures, no further increase in p27(Kip1) expression was observed. Instead, this high WFA dose potently induced vimentin-IF disruption and downregulated α-SMA expression that mimicked WFA activity in TGF-ß-treated RbTCFs that blocked cell contractile activity at submicromolar concentrations. These findings illuminate that localized WFA injection to ocular tissues exerts pharmacological control over the skp2-p27(Kip1) pathway by targeting of soluble vimentin in a model of surgical fibrosis.
format	article
author	Paola Bargagna-Mohan Sunil P Deokule Kyle Thompson John Wizeman Cidambi Srinivasan Sunil Vooturi Uday B Kompella Royce Mohan
author_facet	Paola Bargagna-Mohan Sunil P Deokule Kyle Thompson John Wizeman Cidambi Srinivasan Sunil Vooturi Uday B Kompella Royce Mohan
author_sort	Paola Bargagna-Mohan
title	Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.
title_short	Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.
title_full	Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.
title_fullStr	Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.
title_full_unstemmed	Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.
title_sort	withaferin a effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/9d42ba520c0441daa78792964c03f0a7
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Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis.

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