| ○種別 (必須): | □ | 学術論文 (審査論文)
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| ○言語 (必須): | □ | 英語
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| ○招待 (推奨): |
| ○審査 (推奨): |
| ○カテゴリ (推奨): | □ | 研究
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| ○共著種別 (推奨): | □ | 国際共著 (徳島大学内研究者と国外研究機関所属研究者との共同研究)
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| ○学究種別 (推奨): |
| ○組織 (推奨): |
| ○著者 (必須): | 1. | (英) Zois Christos E (日) (読)
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| 2. | (英) Hendriks Anne M (日) (読)
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| 3. | (英) Haider Syed (日) (読)
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| 4. | (英) Pires Elisabete (日) (読)
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| 5. | (英) Bridges Esther (日) (読)
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| 6. | (英) Kalamida Dimitra (日) (読)
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| 7. | (英) Voukantsis Dimitrios (日) (読)
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| 8. | (英) Lagerholm B Christoffer (日) (読)
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| 9. | (英) Fehrmann Rudolf S N (日) (読)
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| 10. | (英) den Dunnen Wilfred F A (日) (読)
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| 11. | (英) Tarasov Andrei I (日) (読)
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| 12. | 馬場 麻人 ([徳島大学.大学院医歯薬学研究部.歯学域.口腔科学部門.基礎歯学系.口腔顎顔面形態学])
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| 13. | (英) Morris John (日) (読)
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| 14. | (英) Buffa Francesca M (日) (読)
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| 15. | (英) McCullagh James S O (日) (読)
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| 16. | (英) Jalving Mathilde (日) (読)
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| 17. | (英) Harris Adrian L (日) (読)
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| ○題名 (必須): | □ | (英) Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation. (日)
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| ○要約 (任意): | □ | (英) 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. (日)
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| ○キーワード (推奨): | 1. | (英) Adenosine Triphosphate (日) (読)
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| 2. | (英) Glioblastoma (日) (読)
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| 3. | (英) Glucose (日) (読)
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| 4. | (英) Glycogen (日) (読)
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| 5. | (英) Glycogen Phosphorylase (日) (読)
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| 6. | (英) Humans (日) (読)
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| 7. | (英) Liver (日) (読)
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| 8. | (英) Protein Isoforms (日) (読)
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| 9. | (英) RNA, Messenger (日) (読)
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| ○発行所 (推奨): |
| ○誌名 (必須): | □ | Cell Death & Disease ([Nature Publishing Group])
(eISSN: 2041-4889)
| ○ISSN (任意): | □ | 2041-4889
ISSN: 2041-4889
(eISSN: 2041-4889) Title: Cell death & diseaseTitle(ISO): Cell Death DisPublisher: Springer Nature (NLM Catalog)
(Scopus)
(CrossRef)
(Scopus information is found. [need login]) | [継承] |
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| ○巻 (必須): | □ | 13
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| ○号 (必須): | □ | 6
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| ○頁 (必須): | □ | 573 573
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| ○年月日 (必須): | □ | 西暦 2022年 6月 28日 (令和 4年 6月 28日)
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| ○URL (任意): |
| ○DOI (任意): | □ | 10.1038/s41419-022-05005-2 (→Scopusで検索)
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| ○PMID (任意): | □ | 35764612 (→Scopusで検索)
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| ○備考 (任意): | 1. | (英) PublicationType: Journal Article (日)
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