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Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma

Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in...

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Autores principales: Sato, Tomonori, Kawasaki, Yoshihide, Maekawa, Masamitsu, Takasaki, Shinya, Morozumi, Kento, Sato, Masahiko, Shimada, Shuichi, Kawamorita, Naoki, Yamashita, Shinichi, Mitsuzuka, Koji, Mano, Nariyasu, Ito, Akihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821950/
https://www.ncbi.nlm.nih.gov/pubmed/33374949
http://dx.doi.org/10.3390/metabo11010001
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author Sato, Tomonori
Kawasaki, Yoshihide
Maekawa, Masamitsu
Takasaki, Shinya
Morozumi, Kento
Sato, Masahiko
Shimada, Shuichi
Kawamorita, Naoki
Yamashita, Shinichi
Mitsuzuka, Koji
Mano, Nariyasu
Ito, Akihiro
author_facet Sato, Tomonori
Kawasaki, Yoshihide
Maekawa, Masamitsu
Takasaki, Shinya
Morozumi, Kento
Sato, Masahiko
Shimada, Shuichi
Kawamorita, Naoki
Yamashita, Shinichi
Mitsuzuka, Koji
Mano, Nariyasu
Ito, Akihiro
author_sort Sato, Tomonori
collection PubMed
description Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.
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spelling pubmed-78219502021-01-23 Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma Sato, Tomonori Kawasaki, Yoshihide Maekawa, Masamitsu Takasaki, Shinya Morozumi, Kento Sato, Masahiko Shimada, Shuichi Kawamorita, Naoki Yamashita, Shinichi Mitsuzuka, Koji Mano, Nariyasu Ito, Akihiro Metabolites Article Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells. MDPI 2020-12-22 /pmc/articles/PMC7821950/ /pubmed/33374949 http://dx.doi.org/10.3390/metabo11010001 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sato, Tomonori
Kawasaki, Yoshihide
Maekawa, Masamitsu
Takasaki, Shinya
Morozumi, Kento
Sato, Masahiko
Shimada, Shuichi
Kawamorita, Naoki
Yamashita, Shinichi
Mitsuzuka, Koji
Mano, Nariyasu
Ito, Akihiro
Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma
title Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma
title_full Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma
title_fullStr Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma
title_full_unstemmed Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma
title_short Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma
title_sort metabolomic analysis to elucidate mechanisms of sunitinib resistance in renal cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821950/
https://www.ncbi.nlm.nih.gov/pubmed/33374949
http://dx.doi.org/10.3390/metabo11010001
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