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Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA

Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and p...

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Autores principales: Serguienko, Anastassia, Grad, Iwona, Wennerstrøm, Anna B., Meza-Zepeda, Leonardo A., Thiede, Bernd, Stratford, Eva W., Myklebost, Ola, Munthe, Else
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385863/
https://www.ncbi.nlm.nih.gov/pubmed/25669981
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author Serguienko, Anastassia
Grad, Iwona
Wennerstrøm, Anna B.
Meza-Zepeda, Leonardo A.
Thiede, Bernd
Stratford, Eva W.
Myklebost, Ola
Munthe, Else
author_facet Serguienko, Anastassia
Grad, Iwona
Wennerstrøm, Anna B.
Meza-Zepeda, Leonardo A.
Thiede, Bernd
Stratford, Eva W.
Myklebost, Ola
Munthe, Else
author_sort Serguienko, Anastassia
collection PubMed
description Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer. We show that let-7a down-regulates key anabolic enzymes and increases both oxidative phosphorylation and glycolysis in triple-negative breast cancer and metastatic melanoma cell lines. Strikingly, the accelerated glycolysis coexists with drastically reduced cancer features. Moreover, let-7a causes mitochondrial ROS production concomitant with the up-regulation of oxidative stress responsive genes. To exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the chemotherapeutic drug doxorubicin. In both cancer types let-7a increased cell sensitivity to doxorubicin. Pre-treatment with N-acetyl cysteine (NAC) totally abolished this effect, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We thus have demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells, further expanding its therapeutic potential.
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spelling pubmed-43858632015-04-14 Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA Serguienko, Anastassia Grad, Iwona Wennerstrøm, Anna B. Meza-Zepeda, Leonardo A. Thiede, Bernd Stratford, Eva W. Myklebost, Ola Munthe, Else Oncotarget Research Paper Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer. We show that let-7a down-regulates key anabolic enzymes and increases both oxidative phosphorylation and glycolysis in triple-negative breast cancer and metastatic melanoma cell lines. Strikingly, the accelerated glycolysis coexists with drastically reduced cancer features. Moreover, let-7a causes mitochondrial ROS production concomitant with the up-regulation of oxidative stress responsive genes. To exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the chemotherapeutic drug doxorubicin. In both cancer types let-7a increased cell sensitivity to doxorubicin. Pre-treatment with N-acetyl cysteine (NAC) totally abolished this effect, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We thus have demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells, further expanding its therapeutic potential. Impact Journals LLC 2014-12-29 /pmc/articles/PMC4385863/ /pubmed/25669981 Text en Copyright: © 2015 Serguienko et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Serguienko, Anastassia
Grad, Iwona
Wennerstrøm, Anna B.
Meza-Zepeda, Leonardo A.
Thiede, Bernd
Stratford, Eva W.
Myklebost, Ola
Munthe, Else
Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA
title Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA
title_full Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA
title_fullStr Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA
title_full_unstemmed Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA
title_short Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA
title_sort metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microrna
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385863/
https://www.ncbi.nlm.nih.gov/pubmed/25669981
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