There is an urgent need for new therapeutic avenues to improve the outcome of patients with
glioblastoma multiforme (GBM). Current studies have suggested that
cucurbitacin I, a natural selective inhibitor of JAK2/STAT3, has a potent anticancer effect on a variety of
cancer cell types. This study showed that autophagy and apoptosis were induced by
cucurbitacin I. Exposure of GBM cells to
cucurbitacin I resulted in pronounced apoptotic cell death through activating bcl-2 family
proteins. Cells treatment with
cucurbitacin I up-regulated
Beclin 1 and triggered autophagosome formation and accumulation as well as conversion of LC3I to LC3II. Activation of the
AMP-activated protein kinase/
mammalian target of rapamycin/
p70S6K pathway, but not the PI3K/AKT pathway, occurred in autophagy induced by
cucurbitacin I, which was accompanied by decreased
hypoxia-inducible factor 1α. Stable overexpression of
hypoxia-inducible factor 1α induced by
FG-4497 prevented
cucurbitacin I-induced autophagy and down-regulation of bcl-2. Knockdown of
beclin 1 or treatment with the autophagy inhibitor
3-methyladenine also inhibited autophagy induced by
cucurbitacin I. A coimmunoprecipitation assay showed that the interaction of Bcl-2 and
Beclin 1/hVps34 decreased markedly in cells treated with
cucurbitacin I. Furthermore, knockdown of
beclin 1 or treatment with the lysosome inhibitor
chloroquine sensitized
cancer cells to
cucurbitacin I-induced apoptosis. Finally, a xenograft model provided additional evidence for the occurrence of
cucurbitacin I-induced apoptosis and autophagy in vitro. Our findings provide new insights into the molecular mechanisms underlying
cucurbitacin I-mediated GBM cell death and may provide an efficacious
therapy for patients harboring GBM.