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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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Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with -glutamylcyclotransferase (GGCT) in the cytoplasm and repressing the transcriptional activities of the p21 Waf1/Cip (p21) gene in the nucleus. The cytotoxic drug fluorizoline binds to PHB1/2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of fluorizoline is not fully elucidated. In the present study, we first show that fluorizoline induces p21 expression in several human cancer cell lines, including MCF7 breast cancer cells. Treatment of MCF7 cells with fluorizoline suppressed proliferation and prevented cells from entering into the DNA synthesis phase. Knockdown of p21 rescued the suppressed proliferation, indicating that fluorizoline inhibited MCF7 cell growth via the induction of p21. Overexpression of PHB2 in MCF7 cells prevented the induction of p21 expression by fluorizoline, and restored the antiproliferative effects and blockade of cell cycle progression. Moreover, treatment of MCF7 cells with fluorizoline inhibited the interaction between endogenous PHB2 and GGCT proteins, and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting PHB2 with fluorizoline induces the expression of p21 and consequently blocks proliferation of cancer cells.