Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation

Christos E Zois, Anne M Hendriks, Syed Haider, Elisabete Pires, Esther Bridges, Dimitra Kalamida, Dimitrios Voukantsis, B Christoffer Lagerholm, Rudolf S N Fehrmann, Wilfred F A den Dunnen, Andrei I Tarasov, Otto Baba, John Morris, Francesca M Buffa, James S O McCullagh, Mathilde Jalving, Adrian L Harris

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Abstract

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. [Abstract copyright: © 2022. The Author(s).]
Original languageEnglish
Article number573
Pages (from-to)573
Number of pages15
JournalCell Death and Disease
Volume13
Issue number6
Early online date28 Jun 2022
DOIs
Publication statusPublished - 28 Jun 2022

Bibliographical note

Funding Information:
We thank Professor Wojciech Niedzwiedz for the discussions and technical help. We thank Coby Meijer en Natalia Peñaranda Fajardo for their assistance with conducting and analysing the immunohistochemical stains. This research was supported by funding from Cancer Research UK (C19591/A19076; D.C.I.G.), Oxford NIHR Biomedical Research Centre, Breast Cancer Research Foundation (C.E.Z, A.L.H.), Kennington Cancer Fund (A.L.H.), Stichting De Drie Lichten (AMH), Willem Meindert de Hoop Stichting (AMH). Spinning disc confocal imaging was carried out in the Wolfson Imaging Centre Oxford which was supported by the MRC (MC_UU_12009; MC_UU_12010), the Wolfson Foundation (18272), and the Wellcome Trust (Micron 107457/Z/15Z).

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Adenosine Triphosphate
  • Glioblastoma/genetics
  • Glucose/pharmacology
  • Glycogen/metabolism
  • Glycogen Phosphorylase/genetics
  • Humans
  • Liver/metabolism
  • Protein Isoforms
  • RNA, Messenger

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