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Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy

Melanoma is a current worldwide problem, as its incidence is increasing. In the last years, several studies have shown that melanoma cells display high levels of autophagy, a self-degradative process that can promote survival leading to drug resistance. Consequently, autophagy regulation represents...

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Autores principales: Bustos, Silvina Odete, da Silva Pereira, Gustavo José, de Freitas Saito, Renata, Gil, Cristiane Damas, Zanatta, Daniela Bertolli, Smaili, Soraya Soubhi, Chammas, Roger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865690/
https://www.ncbi.nlm.nih.gov/pubmed/29581864
http://dx.doi.org/10.18632/oncotarget.24516
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author Bustos, Silvina Odete
da Silva Pereira, Gustavo José
de Freitas Saito, Renata
Gil, Cristiane Damas
Zanatta, Daniela Bertolli
Smaili, Soraya Soubhi
Chammas, Roger
author_facet Bustos, Silvina Odete
da Silva Pereira, Gustavo José
de Freitas Saito, Renata
Gil, Cristiane Damas
Zanatta, Daniela Bertolli
Smaili, Soraya Soubhi
Chammas, Roger
author_sort Bustos, Silvina Odete
collection PubMed
description Melanoma is a current worldwide problem, as its incidence is increasing. In the last years, several studies have shown that melanoma cells display high levels of autophagy, a self-degradative process that can promote survival leading to drug resistance. Consequently, autophagy regulation represents a challenge for cancer therapy. Herein, we showed that galectin-3 (Gal-3), a β-galactoside binding lectin which is often lost along melanoma progression, is a negative regulator of autophagy in melanoma cells. Our data demonstrated that Gal-3(low/negative) cells were more resistant to the inhibition of the activity of the cancer driver gene BRAF(V600E) by vemurafenib (PLX4032). Interestingly, in these cells, starvation caused further LC3-II accumulation in cells exposed to chloroquine, which inhibits the degradative step in autophagy. In addition, Gal-3 (low/negative) tumor cells accumulated more LC3-II than Gal-3 (high) tumor cells in vivo. Resistance of Gal-3(low/negative) cells was associated with increased production of superoxide and activation of the Endoplasmic Reticulum (ER) stress response, as evaluated by accumulation of GRP78. Pharmacological inhibition of autophagy with bafilomycin A reversed the relative resistance of Gal-3(low/negative) cells to vemurafenib treatment. Taken together, these results show that the autophagic flux is dependent on Gal-3 levels, which attenuate the prosurvival role of autophagy.
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spelling pubmed-58656902018-03-26 Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy Bustos, Silvina Odete da Silva Pereira, Gustavo José de Freitas Saito, Renata Gil, Cristiane Damas Zanatta, Daniela Bertolli Smaili, Soraya Soubhi Chammas, Roger Oncotarget Research Paper Melanoma is a current worldwide problem, as its incidence is increasing. In the last years, several studies have shown that melanoma cells display high levels of autophagy, a self-degradative process that can promote survival leading to drug resistance. Consequently, autophagy regulation represents a challenge for cancer therapy. Herein, we showed that galectin-3 (Gal-3), a β-galactoside binding lectin which is often lost along melanoma progression, is a negative regulator of autophagy in melanoma cells. Our data demonstrated that Gal-3(low/negative) cells were more resistant to the inhibition of the activity of the cancer driver gene BRAF(V600E) by vemurafenib (PLX4032). Interestingly, in these cells, starvation caused further LC3-II accumulation in cells exposed to chloroquine, which inhibits the degradative step in autophagy. In addition, Gal-3 (low/negative) tumor cells accumulated more LC3-II than Gal-3 (high) tumor cells in vivo. Resistance of Gal-3(low/negative) cells was associated with increased production of superoxide and activation of the Endoplasmic Reticulum (ER) stress response, as evaluated by accumulation of GRP78. Pharmacological inhibition of autophagy with bafilomycin A reversed the relative resistance of Gal-3(low/negative) cells to vemurafenib treatment. Taken together, these results show that the autophagic flux is dependent on Gal-3 levels, which attenuate the prosurvival role of autophagy. Impact Journals LLC 2018-02-16 /pmc/articles/PMC5865690/ /pubmed/29581864 http://dx.doi.org/10.18632/oncotarget.24516 Text en Copyright: © 2018 Bustos et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Bustos, Silvina Odete
da Silva Pereira, Gustavo José
de Freitas Saito, Renata
Gil, Cristiane Damas
Zanatta, Daniela Bertolli
Smaili, Soraya Soubhi
Chammas, Roger
Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy
title Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy
title_full Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy
title_fullStr Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy
title_full_unstemmed Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy
title_short Galectin-3 sensitized melanoma cell lines to vemurafenib (PLX4032) induced cell death through prevention of autophagy
title_sort galectin-3 sensitized melanoma cell lines to vemurafenib (plx4032) induced cell death through prevention of autophagy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865690/
https://www.ncbi.nlm.nih.gov/pubmed/29581864
http://dx.doi.org/10.18632/oncotarget.24516
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