Metabolomics

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Inhibition of glioblastoma cell proliferation and invasion by the choline-kinase inhibitor JAS239 varies with cell type and hypoxia.


ABSTRACT:

BACKGROUND: Elevated choline kinase alpha (ChoK) is observed in most solid tumours including glioblastomas (GBM), yet until recently, inhibitors of ChoK have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with GBM therapy resistance, we hypothesised that tumour hypoxia could be responsible for such limitations. We therefore evaluated in GBM cells, the effect of hypoxia on the function of JAS239, a potent ChoK inhibitor.

METHODS: Rodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 hours of hypoxia conditioning and treated with JAS239 for 24 hours. NMR metabolomic measurements and analyses were performed to evaluate the signalling pathways involved. In addition, cell proliferation, cell cycle progression and cell invasion were measured in cell monolayers and 3D spheroids, with or without JAS239 treatment in normoxic or hypoxic cells to assess how hypoxia affects JAS239 function.

RESULTS: Hypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, JAS239 effects were variable depending on the cell line, reflecting the inherent heterogeneity observed in GBMs.

CONCLUSION: Our findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit proliferation and alter cell invasion. These results may be useful for the design of new therapeutic strategies based on ChoK inhibition that can act on multiple pro-tumorigenic features.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR) -

SUBMITTER: Marie Margaret Phelan 

PROVIDER: MTBLS6212 | MetaboLights | 2024-06-18

REPOSITORIES: MetaboLights

Dataset's files

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Action DRS
MTBLS6212 Other
FILES Other
a_MTBLS6212_NMR___metabolite_profiling.txt Txt
i_Investigation.txt Txt
m_MTBLS6212_NMR___metabolite_profiling_v2_maf.tsv Tabular
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Publications

Inhibition of glioblastoma cell proliferation and invasion by the choline-kinase inhibitor JAS239 varies with cell type and hypoxia.

Louise Kelly Claire C   Wydrzynska Martyna M   Phelan Marie M MM   Osharovich Sofya S   Delikatny Edward J EJ   Sée Violaine V   Poptani Harish H  

bioRxiv : the preprint server for biology 20240120


<h4>Background</h4>Elevated choline kinase alpha (ChoK) is observed in most solid tumours including glioblastomas (GBM), yet until recently, inhibitors of ChoK have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with GBM therapy resistance, we hypothesised that tumour hypoxia could be responsible for such limitations. We therefore evaluated in GBM cells, the effect of hypoxia on the function of JAS239, a potent ChoK inhibitor.<h4>Methods</h4>Rodent (F98 and 9L) and  ...[more]

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