| Item type |
文献 / Documents(1) |
| 公開日 |
2024-10-22 |
| アクセス権 |
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|
アクセス権 |
open access |
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アクセス権URI |
http://purl.org/coar/access_right/c_abf2 |
| 資源タイプ |
|
|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| item_1722929371688 |
|
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|
識別子タイプ |
DOI |
|
|
関連識別子 |
https://doi.org/10.1038/s41419-022-05005-2 |
|
|
言語 |
ja |
|
|
関連名称 |
10.1038/s41419-022-05005-2 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation |
|
言語 |
en |
| 著者 |
Zois, Christos E.
Hendriks, Anne M.
Haider, Syed
Pires, Elisabete
Bridges, Esther
Kalamida, Dimitra
Voukantsis, Dimitrios
Lagerholm, B. Christoffer
Fehrmann, Rudolf S.N.
Dunnen, Wilfred F. A.den
Tarasov, Andrei I.
馬場, 麻人
Morris, John
Buffa, Francesca M.
McCullagh, James S. O.
Jalving, Mathilde
Harris, Adrian L.
|
| 抄録 |
|
|
内容記述タイプ |
Abstract |
|
内容記述 |
Channelling of glucose via glycogen, known as the glycogen shunt, may play an important role in the metabolism of brain tumours, especially in hypoxic conditions. We aimed to dissect the role of glycogen degradation in glioblastoma (GBM) response to ionising radiation (IR). Knockdown of the glycogen phosphorylase liver isoform (PYGL), but not the brain isoform (PYGB), decreased clonogenic growth and survival of GBM cell lines and sensitised them to IR doses of 10–12 Gy. Two to five days after IR exposure of PYGL knockdown GBM cells, mitotic catastrophy and a giant multinucleated cell morphology with senescence-like phenotype developed. The basal levels of the lysosomal enzyme alpha-acid glucosidase (GAA), essential for autolysosomal glycogen degradation, and the lipidated forms of gamma-aminobutyric acid receptor-associated protein-like (GABARAPL1 and GABARAPL2) increased in shPYGL U87MG cells, suggesting a compensatory mechanism of glycogen degradation. In response to IR, dysregulation of autophagy was shown by accumulation of the p62 and the lipidated form of GABARAPL1 and GABARAPL2 in shPYGL U87MG cells. IR increased the mitochondrial mass and the colocalisation of mitochondria with lysosomes in shPYGL cells, thereby indicating reduced mitophagy. These changes coincided with increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase 2, slower ATP generation in response to glucose loading and progressive loss of oxidative phosphorylation. The resulting metabolic deficiencies affected the availability of ATP required for mitosis, resulting in the mitotic catastrophy observed in shPYGL cells following IR. PYGL mRNA and protein levels were higher in human GBM than in normal human brain tissues and high PYGL mRNA expression in GBM correlated with poor patient survival. In conclusion, we show a major new role for glycogen metabolism in GBM cancer. Inhibition of glycogen degradation sensitises GBM cells to high-dose IR indicating that PYGL is a potential novel target for the treatment of GBMs. |
|
言語 |
en |
| bibliographic_information |
en : Cell Death & Disease
巻 13,
p. 573,
発行日 2022-06-28
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| 収録物ID |
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|
収録物識別子タイプ |
EISSN |
|
収録物識別子 |
20414889 |
| 出版者 |
|
|
出版者 |
Springer Nature |
|
言語 |
en |
| item_10001_rights_15 |
|
|
言語 |
en |
|
権利情報 |
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. The 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. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| item_1723180141928 |
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|
識別子 |
386342 |
|
識別子タイプ |
URI |
| 言語 |
|
|
言語 |
eng |
cdd_13_573.pdf (6.7 MB)
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