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Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition

Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a con...

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Autores principales: Cevatemre, Buse, Ulukaya, Engin, Dere, Egemen, Dilege, Sukru, Acilan, Ceyda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785343/
https://www.ncbi.nlm.nih.gov/pubmed/35083212
http://dx.doi.org/10.3389/fcell.2021.738916
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author Cevatemre, Buse
Ulukaya, Engin
Dere, Egemen
Dilege, Sukru
Acilan, Ceyda
author_facet Cevatemre, Buse
Ulukaya, Engin
Dere, Egemen
Dilege, Sukru
Acilan, Ceyda
author_sort Cevatemre, Buse
collection PubMed
description Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGFβRI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.
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spelling pubmed-87853432022-01-25 Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition Cevatemre, Buse Ulukaya, Engin Dere, Egemen Dilege, Sukru Acilan, Ceyda Front Cell Dev Biol Cell and Developmental Biology Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGFβRI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment. Frontiers Media S.A. 2022-01-04 /pmc/articles/PMC8785343/ /pubmed/35083212 http://dx.doi.org/10.3389/fcell.2021.738916 Text en Copyright © 2022 Cevatemre, Ulukaya, Dere, Dilege and Acilan. 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 Cell and Developmental Biology
Cevatemre, Buse
Ulukaya, Engin
Dere, Egemen
Dilege, Sukru
Acilan, Ceyda
Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition
title Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition
title_full Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition
title_fullStr Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition
title_full_unstemmed Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition
title_short Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition
title_sort pyruvate dehydrogenase contributes to drug resistance of lung cancer cells through epithelial mesenchymal transition
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785343/
https://www.ncbi.nlm.nih.gov/pubmed/35083212
http://dx.doi.org/10.3389/fcell.2021.738916
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