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Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase

In addition to its well-established immunosuppressive actions, tryptophan 2,3-dioxygenase (TDO) appears to elicit direct effects on tumor cell function. Although TDO has been associated with cancer stemness, its involvement in melanoma stem cell biology remains largely unknown. Since we showed that...

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Autores principales: Cecchi, Marta, Mannini, Antonella, Lapucci, Andrea, Silvano, Angela, Lulli, Matteo, Luceri, Cristina, D’Ambrosio, Mario, Chiarugi, Alberto, Eid, Ali H., Parenti, Astrid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280025/
https://www.ncbi.nlm.nih.gov/pubmed/35847038
http://dx.doi.org/10.3389/fphar.2022.911019
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author Cecchi, Marta
Mannini, Antonella
Lapucci, Andrea
Silvano, Angela
Lulli, Matteo
Luceri, Cristina
D’Ambrosio, Mario
Chiarugi, Alberto
Eid, Ali H.
Parenti, Astrid
author_facet Cecchi, Marta
Mannini, Antonella
Lapucci, Andrea
Silvano, Angela
Lulli, Matteo
Luceri, Cristina
D’Ambrosio, Mario
Chiarugi, Alberto
Eid, Ali H.
Parenti, Astrid
author_sort Cecchi, Marta
collection PubMed
description In addition to its well-established immunosuppressive actions, tryptophan 2,3-dioxygenase (TDO) appears to elicit direct effects on tumor cell function. Although TDO has been associated with cancer stemness, its involvement in melanoma stem cell biology remains largely unknown. Since we showed that by upregulating TDO, dexamethasone (dex) promotes proliferation and migration of SK-Mel-28 human melanoma cells, we sought to investigate dex effects on melanoma spherogenesis and stemness, and whether these events are mediated by TDO. We demonstrate here that dex significantly upregulates TDO in A375, a more aggressive melanoma cell line, confirming that dex effects are not limited to SK-Mel-28 cells. Moreover, dex stimulates spherogenesis of both cell lines, which is mediated by TDO, evident by its suppression with 680C91, a TDO inhibitor. The formed melanospheres appear to be enriched with embryonic stem cell marker mRNAs, the expression of which is potentiated by dex. Expression of cancer stem cell markers (CD133, CD44, ganglioside GD2) was significantly increased in A375 spheres, as detected by flow cytometry. Taken together, our results suggest that TDO could represent a promising target in the management of melanoma and that dex, routinely used as a co-medication also in advanced melanoma, may stimulate melanoma cell function/tumor-supporting properties, a rather debilitating and undesired side effect.
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spelling pubmed-92800252022-07-15 Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase Cecchi, Marta Mannini, Antonella Lapucci, Andrea Silvano, Angela Lulli, Matteo Luceri, Cristina D’Ambrosio, Mario Chiarugi, Alberto Eid, Ali H. Parenti, Astrid Front Pharmacol Pharmacology In addition to its well-established immunosuppressive actions, tryptophan 2,3-dioxygenase (TDO) appears to elicit direct effects on tumor cell function. Although TDO has been associated with cancer stemness, its involvement in melanoma stem cell biology remains largely unknown. Since we showed that by upregulating TDO, dexamethasone (dex) promotes proliferation and migration of SK-Mel-28 human melanoma cells, we sought to investigate dex effects on melanoma spherogenesis and stemness, and whether these events are mediated by TDO. We demonstrate here that dex significantly upregulates TDO in A375, a more aggressive melanoma cell line, confirming that dex effects are not limited to SK-Mel-28 cells. Moreover, dex stimulates spherogenesis of both cell lines, which is mediated by TDO, evident by its suppression with 680C91, a TDO inhibitor. The formed melanospheres appear to be enriched with embryonic stem cell marker mRNAs, the expression of which is potentiated by dex. Expression of cancer stem cell markers (CD133, CD44, ganglioside GD2) was significantly increased in A375 spheres, as detected by flow cytometry. Taken together, our results suggest that TDO could represent a promising target in the management of melanoma and that dex, routinely used as a co-medication also in advanced melanoma, may stimulate melanoma cell function/tumor-supporting properties, a rather debilitating and undesired side effect. Frontiers Media S.A. 2022-06-30 /pmc/articles/PMC9280025/ /pubmed/35847038 http://dx.doi.org/10.3389/fphar.2022.911019 Text en Copyright © 2022 Cecchi, Mannini, Lapucci, Silvano, Lulli, Luceri, D’Ambrosio, Chiarugi, Eid and Parenti. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Cecchi, Marta
Mannini, Antonella
Lapucci, Andrea
Silvano, Angela
Lulli, Matteo
Luceri, Cristina
D’Ambrosio, Mario
Chiarugi, Alberto
Eid, Ali H.
Parenti, Astrid
Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase
title Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase
title_full Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase
title_fullStr Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase
title_full_unstemmed Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase
title_short Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase
title_sort dexamethasone promotes a stem-like phenotype in human melanoma cells via tryptophan 2,3 dioxygenase
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280025/
https://www.ncbi.nlm.nih.gov/pubmed/35847038
http://dx.doi.org/10.3389/fphar.2022.911019
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