Furanodienone overcomes temozolomide resistance in glioblastoma through the downregulation of CSPG4‐Akt‐ERK signalling by inhibiting EGR1‐dependent transcription

Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumour. Patients with GBM respond poorly to chemotherapy and have poor survival outcomes. Neuron‐glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), has been shown to contribute to critical processes, such as cell survival, proliferation, and chemotherapy resistance, during glioma progression. In this study, we found that furanodienone (FUR), a diene‐type sesquiterpene isolated from the rhizomes of Rhizoma curcumae , exhibited a potential cytotoxic effect on temozolomide (TMZ)–resistant GBM cells in vitro by inhibiting CSPG4 and related signalling pathways. Studies investigating the mechanism demonstrated that FUR suppressed CSPG4‐Akt‐ERK signalling, inflammatory responses, and cytokine levels but activated caspase‐dependent pathways and mitochondrial dysfunction. Furthermore, an immunofluorescence assay and a dual‐luciferase reporter assay revealed that inhibition of EGR1‐mediated transcription might have contributed to the FUR‐dependent blockade of CSPG4 signalling and glioma cell survival. These results established a link between FUR‐induced CSPG4 inhibition and the suppression of EGR1‐dependent transcription. Attenuation of ERK1/2 and cytokine signalling might have generated the EGR1‐dependent negative feedback loop of the CSPG4 pathway during FUR‐induced apoptosis. These findings suggested that FUR could be a therapeutic candidate for the treatment of malignant glioma via targeting CSPG4 signalling.