Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models

Abstract The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transiti...

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Autores principales:	Mario Sechi, Rahul K. Lall, Saheed O Afolabi, Anant Singh, Dinesh C. Joshi, Shing-Yan Chiu, Hasan Mukhtar, Deeba N. Syed
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Fisetin Treatment Vemurafenib Melanoma Cultures Inhibit Melanoma Growth WM9 Melanoma Cells Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5e2df20b2938453aa0b4f7b03494c319
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spelling	oai:doaj.org-article:5e2df20b2938453aa0b4f7b03494c3192021-12-02T15:07:50ZFisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models10.1038/s41598-018-33879-w2045-2322https://doaj.org/article/5e2df20b2938453aa0b4f7b03494c3192018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33879-whttps://doaj.org/toc/2045-2322Abstract The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.Mario SechiRahul K. LallSaheed O AfolabiAnant SinghDinesh C. JoshiShing-Yan ChiuHasan MukhtarDeeba N. SyedNature PortfolioarticleFisetin TreatmentVemurafenibMelanoma CulturesInhibit Melanoma GrowthWM9 Melanoma CellsMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fisetin Treatment Vemurafenib Melanoma Cultures Inhibit Melanoma Growth WM9 Melanoma Cells Medicine R Science Q
spellingShingle	Fisetin Treatment Vemurafenib Melanoma Cultures Inhibit Melanoma Growth WM9 Melanoma Cells Medicine R Science Q Mario Sechi Rahul K. Lall Saheed O Afolabi Anant Singh Dinesh C. Joshi Shing-Yan Chiu Hasan Mukhtar Deeba N. Syed Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models
description	Abstract The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.
format	article
author	Mario Sechi Rahul K. Lall Saheed O Afolabi Anant Singh Dinesh C. Joshi Shing-Yan Chiu Hasan Mukhtar Deeba N. Syed
author_facet	Mario Sechi Rahul K. Lall Saheed O Afolabi Anant Singh Dinesh C. Joshi Shing-Yan Chiu Hasan Mukhtar Deeba N. Syed
author_sort	Mario Sechi
title	Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models
title_short	Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models
title_full	Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models
title_fullStr	Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models
title_full_unstemmed	Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models
title_sort	fisetin targets yb-1/rsk axis independent of its effect on erk signaling: insights from in vitro and in vivo melanoma models
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/5e2df20b2938453aa0b4f7b03494c319
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Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models

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