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ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression

Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which ce...

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Autores principales: da Costa, Kelli Monteiro, Freire-de-Lima, Leonardo, da Fonseca, Leonardo Marques, Previato, José Osvaldo, Mendonça-Previato, Lucia, Valente, Raphael do Carmo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093952/
https://www.ncbi.nlm.nih.gov/pubmed/37047018
http://dx.doi.org/10.3390/ijms24076046
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author da Costa, Kelli Monteiro
Freire-de-Lima, Leonardo
da Fonseca, Leonardo Marques
Previato, José Osvaldo
Mendonça-Previato, Lucia
Valente, Raphael do Carmo
author_facet da Costa, Kelli Monteiro
Freire-de-Lima, Leonardo
da Fonseca, Leonardo Marques
Previato, José Osvaldo
Mendonça-Previato, Lucia
Valente, Raphael do Carmo
author_sort da Costa, Kelli Monteiro
collection PubMed
description Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters’ role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-β-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT.
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spelling pubmed-100939522023-04-13 ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression da Costa, Kelli Monteiro Freire-de-Lima, Leonardo da Fonseca, Leonardo Marques Previato, José Osvaldo Mendonça-Previato, Lucia Valente, Raphael do Carmo Int J Mol Sci Article Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters’ role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-β-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT. MDPI 2023-03-23 /pmc/articles/PMC10093952/ /pubmed/37047018 http://dx.doi.org/10.3390/ijms24076046 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
da Costa, Kelli Monteiro
Freire-de-Lima, Leonardo
da Fonseca, Leonardo Marques
Previato, José Osvaldo
Mendonça-Previato, Lucia
Valente, Raphael do Carmo
ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression
title ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression
title_full ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression
title_fullStr ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression
title_full_unstemmed ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression
title_short ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression
title_sort abcb1 and abcc1 function during tgf-β-induced epithelial-mesenchymal transition: relationship between multidrug resistance and tumor progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093952/
https://www.ncbi.nlm.nih.gov/pubmed/37047018
http://dx.doi.org/10.3390/ijms24076046
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