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

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.

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer

“…Furthermore, while control cells are largely resistant to DAB treatment, abrogation of glycogenolysis significantly decreases the survival of Drp1 knockdown cells. Similarly, it has been shown previously that knockdown of glycogen phosphorylase liver isoform (PYGL) sensitizes glioblastoma cells to radiation treatment [ 49 ]. It is of particular interest for future studies to determine if glycogen accumulation also provide survival advantage to cancer cells against other nutrient deprivation conditions.…”

Machine learning-based identification of glycosyltransferase-related mRNAs for improving outcomes and the anti-tumor therapeutic response of gliomas

“…The overexpression of PYGL in GBM tissues was associated with poor survival. Knockdown of PYGL decreased the growth and survival of the GBM cell line ( Zois et al, 2022 ). Our comprehensive analyses revealed that the GRMS was a hazardous biomarker for the prognosis of glioma patients, consistent with previous findings.…”

Synthesis, In Silico and Kinetics Evaluation of N-(β-d-glucopyranosyl)-2-arylimidazole-4(5)-carboxamides and N-(β-d-glucopyranosyl)-4(5)-arylimidazole-2-carboxamides as Glycogen Phosphorylase Inhibitors

“…More specifically, the liver isoform is of interest as it catalyses the breakdown of glycogen into glucose in the liver, the inhibition of which has potential to reduce hyperglycaemia in T2DM patients [6]. Additionally, GP is also considered of promise as a target for other conditions such as myocardial and cerebral ischemias [7,8] and different cancers such as glioblastoma [9][10][11]. Seven different GP ligand-binding sites have been discovered to date: catalytic, allosteric, new allosteric, glycogen storage, inhibitor, benzimidazole and quercetin-binding sites, with the catalytic site being a focal point of research to date [12][13][14][15].…”