Exploiting the metabolic vulnerabilities imposed by glucocorticoids for glioblastoma treatment
Session type: Poster / e-Poster / Silent Theatre session
Synthetic glucocorticoids are a mainstay of the clinical management of brain tumours patients and their anti-inflammatory action is essential to reduce the tumour-associated oedema and its severe symptoms. However, recent clinical studies suggest that high doses of glucocorticoids worsened the overall prognosis of glioblastoma patients. Moreover, the direct biological effects of glucocorticoids on glioblastoma cells have been controversial, and remain poorly understood.
We characterized the effects of clinically relevant doses of dexamethasone on the metabolism of patient-derived glioblastoma cells with the aim to identify metabolic reactions that become essential for dexamethasone-treated glioblastoma cells.
Four patient-derived glioblastoma cell lines at low passages were cultured as monolayer or spheres in the absence of serum and B27, which contains steroids. In all the experiments, cells were cultured in Plasmax (TM), a new advanced medium with physiological concentrations of nutrients. Liquid chromatography-mass spectrometry approaches were used to profile cell metabolism, and the exchange rates of nutrients between cells and medium. The drug-dependent changes in the transcriptome were assessed by RNA sequencing.
All the glioblastoma cells expressed the glucocorticoid receptor which translocated to the nucleus when activated by dexamethasone. The proliferation of glioblastoma cells was significantly impaired (2/4 lines), enhanced (1/4) or unaffected (1/4) by clinically-relevant concentrations of dexamethasone. In line with the divergent effects on proliferation, the transcriptional profile of the dexamethasone-treated cells showed a modest overlap among the 4 lines. The expression of 81 genes was coherently regulated by the drug treatment in 4/4 lines.
The untargeted metabolomics identified 2 metabolites whose levels were significantly increased upon dexamethasone treatment in all 4 cell lines. These features were validated by a targeted approach and the functional implications of these changes are currently under investigation.
Dexamethasone differentially affects the proliferation of glioblastoma cells and it consistently increases the expression and activity of specific metabolic enzymes.