| Abstract |
The prognosis of glioblastoma, which is the most frequent type of adult‑onset malignant brain tumor, is extremely poor. Therefore, novel therapeutic strategies are needed. Previous studies report that JCI‑20679, which is synthesized based on the structure of naturally occurring acetogenin, inhibits mitochondrial complex I and suppresses the growth of various types of cancer cells. However, the efficacy of JCI‑20679 on glioblastoma stem cells (GSCs) is unknown. The present study demonstrated that JCI‑20679 inhibited the growth of GSCs derived from a transposon system‑mediated murine glioblastoma model more efficiently compared with the growth of differentiation‑induced adherent cells, as determined by a trypan blue staining dye exclusion test. The inhibition of proliferation was accompanied by the blockade of cell‑cycle entry into the S‑phase, as assessed by a BrdU incorporation assay. JCI‑20679 decreased the mitochondrial membrane potential, suppressed the oxygen consumption rate and increased mitochondrial reactive oxygen species generation, indicating that JCI‑20679 inhibited mitochondrial activity. The mitochondrial inhibition was revealed to increase phosphorylated (phospho)‑AMPKα levels and decrease nuclear factor of activated T‑cells 2 (NFATc2) expression, and was accompanied by a decrease in calcineurin phosphatase activity. Depletion of phospho‑AMPKα by knockdown of AMPKβ recovered the JCI‑20679‑mediated decrease in NFATc2 expression levels, as determined by western blotting and reverse transcription‑quantitative PCR analysis. Overexpression of NFATc2 recovered the JCI‑20679‑mediated suppression of proliferation, as determined by a trypan blue staining dye exclusion test. These results suggest that JCI‑20679 inhibited mitochondrial oxidative phosphorylation, which activated AMPK and reduced NFATc2 expression levels. Moreover, systemic administration of JCI‑20679 extended the event‑free survival rate in a mouse model transplanted with GSCs. Overall, these results suggested that JCI‑20679 is a potential novel therapeutic agent against glioblastoma.
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