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Title: UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization
Authors: Nakashima, Ryota
Goto, Yoko
Koyasu, Sho  kyouindb  KAKEN_id
Kobayashi, Minoru  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-3843-3584 (unconfirmed)
Morinibu, Akiyo
Yoshimura, Michio  kyouindb  KAKEN_id
Hiraoka, Masahiro
Hammond, Ester M.
Harada, Hiroshi
Author's alias: 中島, 良太
後藤, 容子
子安, 翔
小林, 稔
森鳰, 章代
吉村, 通央
平岡, 真寛
原田, 浩
Keywords: Oncogenes
Radiotherapy
Issue Date: 31-Jul-2017
Publisher: Nature Publishing Group
Journal title: Scientific Reports
Volume: 7
Thesis number: 6879
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.
Rights: © 2017 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
URI: http://hdl.handle.net/2433/227689
DOI(Published Version): 10.1038/s41598-017-06605-1
PubMed ID: 28761052
Appears in Collections:Journal Articles

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