Despite standard treatment with surgery, temozolomide (TMZ) and radiotherapy, the prognosis of high-grade glioma (HGG) remains dismal. Metformin, an anti-diabetic drug has demonstrated anti-tumor effects in gliomas. Interestingly, a recent transcriptomic analysis study showed that interleukin 13 receptor alpha 2 (IL-13Rα2) is highly upregulated in patients with diabetic nephropathy. IL-13Rα2 is also commonly overexpressed in HGG. However, the effect of metformin on IL-13Rα2-expressing glioma cells is currently unknown. Hence, we aim to evaluate the combined treatment of TMZ and metformin in a series of human glioma cells with IL-13Rα2, and other commonly found genetic aberrations for translational purpose.
A series of human glioma cell lines were treated with TMZ, metformin and a combination of TMZ and metformin. Cell viability was determined with CCK-8 assay. The effect of these treatments on key glioma-associated signalling pathways, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR were investigated by immunoblot analysis. Findings were validated through loss-of-function assays.
IL-13Rα2 positive glioma cells were resistant to metformin in a dose-dependent manner. The combination of TMZ and metformin markedly enhanced adenosine monophosphate-activated protein kinase (AMPK) activation in IL-13Rα2-positive glioma cells, compared to IL-13Rα2-null glioma cells. Furthermore, in the combined treatment group, metformin effectively inhibited Akt and mTOR activation induced by TMZ. There was no significant reduction in mTOR and S6K phosphorylation in the combined versus metformin group.
Metformin sensitizes TMZ-resistant cells to increased cell death. The overexpression of IL-13Rα2 in glioma cells could confer resistance against metformin through the enhanced activation of AMPK and Akt pathways. Elucidation of how IL-13Rα2 confers resistance against metformin is important in the potential application of metformin in patients with high-grade glioma.
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Legal entity responsible for the study
National Medical Research Council
All authors have declared no conflicts of interest.