UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization

Abstract Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant propertie...

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Autores principales:	Ryota Nakashima, Yoko Goto, Sho Koyasu, Minoru Kobayashi, Akiyo Morinibu, Michio Yoshimura, Masahiro Hiraoka, Ester M. Hammond, Hiroshi Harada
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0eb813fe8b2c4d88992eb98d2a5ae043
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spelling	oai:doaj.org-article:0eb813fe8b2c4d88992eb98d2a5ae0432021-12-02T12:30:13ZUCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization10.1038/s41598-017-06605-12045-2322https://doaj.org/article/0eb813fe8b2c4d88992eb98d2a5ae0432017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06605-1https://doaj.org/toc/2045-2322Abstract Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming. A luciferase assay to monitor HIF-1 activity demonstrated that the overexpression of UCHL1, but not its deubiquitination activity-deficient mutant (UCHL1 C90S), upregulated HIF-1 activity by stabilizing the regulatory subunit of HIF-1 (HIF-1α) in a murine breast cancer cell line, EMT6. UCHL1 overexpression induced the reprogramming of carbohydrate metabolism and increased NADPH levels in a pentose phosphate pathway (PPP)-dependent manner. The UCHL1-mediated reprogramming elevated intracellular GSH levels, and consequently induced a radioresistant phenotype in a HIF-1-dependent manner. The pharmacological inhibition of PPP canceled the UCHL1-mediated radioresistance. These results collectively suggest that cancer cells acquire antioxidant and radioresistant phenotypes through UCHL1-HIF-1-mediated metabolic reprogramming including the activation of PPP and provide a rational basis for targeting this gene network for radiosensitization.Ryota NakashimaYoko GotoSho KoyasuMinoru KobayashiAkiyo MorinibuMichio YoshimuraMasahiro HiraokaEster M. HammondHiroshi HaradaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ryota Nakashima Yoko Goto Sho Koyasu Minoru Kobayashi Akiyo Morinibu Michio Yoshimura Masahiro Hiraoka Ester M. Hammond Hiroshi Harada UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
description	Abstract Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming. A luciferase assay to monitor HIF-1 activity demonstrated that the overexpression of UCHL1, but not its deubiquitination activity-deficient mutant (UCHL1 C90S), upregulated HIF-1 activity by stabilizing the regulatory subunit of HIF-1 (HIF-1α) in a murine breast cancer cell line, EMT6. UCHL1 overexpression induced the reprogramming of carbohydrate metabolism and increased NADPH levels in a pentose phosphate pathway (PPP)-dependent manner. The UCHL1-mediated reprogramming elevated intracellular GSH levels, and consequently induced a radioresistant phenotype in a HIF-1-dependent manner. The pharmacological inhibition of PPP canceled the UCHL1-mediated radioresistance. These results collectively suggest that cancer cells acquire antioxidant and radioresistant phenotypes through UCHL1-HIF-1-mediated metabolic reprogramming including the activation of PPP and provide a rational basis for targeting this gene network for radiosensitization.
format	article
author	Ryota Nakashima Yoko Goto Sho Koyasu Minoru Kobayashi Akiyo Morinibu Michio Yoshimura Masahiro Hiraoka Ester M. Hammond Hiroshi Harada
author_facet	Ryota Nakashima Yoko Goto Sho Koyasu Minoru Kobayashi Akiyo Morinibu Michio Yoshimura Masahiro Hiraoka Ester M. Hammond Hiroshi Harada
author_sort	Ryota Nakashima
title	UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
title_short	UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
title_full	UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
title_fullStr	UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
title_full_unstemmed	UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
title_sort	uchl1-hif-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0eb813fe8b2c4d88992eb98d2a5ae043
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UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization

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