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Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells

The transcription factor FOXO3 is associated with poor outcome in high-stage neuroblastoma (NB), as it facilitates chemoprotection and tumor angiogenesis. In other tumor entities, FOXO3 stimulates metastasis formation, one of the biggest challenges in the treatment of aggressive NB. However, the imp...

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Autores principales: Salcher, Stefan, Spoden, Gilles, Huber, Julia M., Golderer, Georg, Lindner, Herbert, Ausserlechner, Michael J., Kiechl-Kohlendorfer, Ursula, Geiger, Kathrin, Obexer, Petra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017090/
https://www.ncbi.nlm.nih.gov/pubmed/31861249
http://dx.doi.org/10.3390/cells9010001
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author Salcher, Stefan
Spoden, Gilles
Huber, Julia M.
Golderer, Georg
Lindner, Herbert
Ausserlechner, Michael J.
Kiechl-Kohlendorfer, Ursula
Geiger, Kathrin
Obexer, Petra
author_facet Salcher, Stefan
Spoden, Gilles
Huber, Julia M.
Golderer, Georg
Lindner, Herbert
Ausserlechner, Michael J.
Kiechl-Kohlendorfer, Ursula
Geiger, Kathrin
Obexer, Petra
author_sort Salcher, Stefan
collection PubMed
description The transcription factor FOXO3 is associated with poor outcome in high-stage neuroblastoma (NB), as it facilitates chemoprotection and tumor angiogenesis. In other tumor entities, FOXO3 stimulates metastasis formation, one of the biggest challenges in the treatment of aggressive NB. However, the impact of FOXO3 on the metastatic potential of neuronal tumor cells remains largely unknown. In the present study, we uncover the small leucine-rich proteoglycan family member lumican (LUM) as a FOXO3-regulated gene that stimulates cellular migration in NB. By a drug-library screen we identified the small molecular weight compound repaglinide (RPG) as a putative FOXO3 inhibitor. Here, we verify that RPG binds to the FOXO3-DNA-binding-domain (DBD) and thereby silences the transcriptional activity of FOXO3. Consistent with the concept that the FOXO3/LUM axis enhances the migratory capacity of aggressive NB cells, we demonstrate that stable knockdown of LUM abrogates the FOXO3-mediated increase in cellular migration. Importantly, FOXO3 inhibition by RPG represses the binding of FOXO3 to the LUM promoter, inhibits FOXO3-mediated LUM RNA and protein expression, and efficiently abrogates FOXO3-triggered cellular “wound healing” as well as spheroid-based 3D-migration. Thus, silencing the FOXO3/LUM axis by the FDA-approved compound RPG represents a promising strategy for novel therapeutic interventions in NB and other FOXO3-dependent tumors.
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spelling pubmed-70170902020-02-28 Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells Salcher, Stefan Spoden, Gilles Huber, Julia M. Golderer, Georg Lindner, Herbert Ausserlechner, Michael J. Kiechl-Kohlendorfer, Ursula Geiger, Kathrin Obexer, Petra Cells Article The transcription factor FOXO3 is associated with poor outcome in high-stage neuroblastoma (NB), as it facilitates chemoprotection and tumor angiogenesis. In other tumor entities, FOXO3 stimulates metastasis formation, one of the biggest challenges in the treatment of aggressive NB. However, the impact of FOXO3 on the metastatic potential of neuronal tumor cells remains largely unknown. In the present study, we uncover the small leucine-rich proteoglycan family member lumican (LUM) as a FOXO3-regulated gene that stimulates cellular migration in NB. By a drug-library screen we identified the small molecular weight compound repaglinide (RPG) as a putative FOXO3 inhibitor. Here, we verify that RPG binds to the FOXO3-DNA-binding-domain (DBD) and thereby silences the transcriptional activity of FOXO3. Consistent with the concept that the FOXO3/LUM axis enhances the migratory capacity of aggressive NB cells, we demonstrate that stable knockdown of LUM abrogates the FOXO3-mediated increase in cellular migration. Importantly, FOXO3 inhibition by RPG represses the binding of FOXO3 to the LUM promoter, inhibits FOXO3-mediated LUM RNA and protein expression, and efficiently abrogates FOXO3-triggered cellular “wound healing” as well as spheroid-based 3D-migration. Thus, silencing the FOXO3/LUM axis by the FDA-approved compound RPG represents a promising strategy for novel therapeutic interventions in NB and other FOXO3-dependent tumors. MDPI 2019-12-18 /pmc/articles/PMC7017090/ /pubmed/31861249 http://dx.doi.org/10.3390/cells9010001 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Salcher, Stefan
Spoden, Gilles
Huber, Julia M.
Golderer, Georg
Lindner, Herbert
Ausserlechner, Michael J.
Kiechl-Kohlendorfer, Ursula
Geiger, Kathrin
Obexer, Petra
Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells
title Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells
title_full Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells
title_fullStr Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells
title_full_unstemmed Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells
title_short Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells
title_sort repaglinide silences the foxo3/lumican axis and represses the associated metastatic potential of neuronal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017090/
https://www.ncbi.nlm.nih.gov/pubmed/31861249
http://dx.doi.org/10.3390/cells9010001
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