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

Abstract

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.

Molecular Mechanism of Helicobacter pylori-Induced Gastric Cancer

“…Activated SHP2 induces activation of the Ras (for rat sarcoma virus)–ErK (extracellular signal-regulated kinases) signaling pathway leading to mitogenic response [ 52 ]. In the nucleus, ERK phosphorylates and activates the transcription activator ELK1 (for E-26-like protein-1) [ 53 ]. Activated ELK1 along with SRF (serum response factor) binds to serum response elements (SREs) and induces the expression of immediate early genes including c-Fos and c-Jun [ 54 – 56 ].…”

Investigating Glioblastoma Response to Hypoxia

“…EGR1 is a Cys2-His2-type zinc finger transcription factor that in GB cell lines has been shown to bind to GC-rich sites of the TGF-β promotor leading to decreased proliferation and suppressing transformation [ 68 ]. In contrast, another study showed that EGR1 induces U251 cell migration via activation of fibronectin [ 69 ]; and other reports indicated that EGR1 confers temozolomide resistance in GB [ 70 , 71 ]. EGR1 has also been shown to promote a glioma stem cell-like phenotype [ 72 , 73 ].…”

CARs: Beyond T Cells and T Cell-Derived Signaling Domains

“…In another study aiming to prove the importance of vehicle-specific CAR design, two anti-CD5 CARs with a 4-1BB/CD3ζ (a T cell-associated) or a 2B4/CD3ζ (rather NK cell-specific) intracellular tail were tested [227]. Both were transduced into NK cells and employed in a CD5 + T cell acute lymphoblastic leukemia (T-ALL) mouse model, where they both exhibited specific cytotoxicity and prolonged survival of the mice.…”

“…Both were transduced into NK cells and employed in a CD5 + T cell acute lymphoblastic leukemia (T-ALL) mouse model, where they both exhibited specific cytotoxicity and prolonged survival of the mice. The 2B4/CD3ζ CAR displayed greater lytic capacity but also elevated toxicity against non-malignant T cells [227].…”