Cucurbitacin I induces protective autophagy in glioblastoma in vitro and in vivo.
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.
['Yuan|Guang|G|', 'Yan|Shao-Feng|SF|', 'Xue|Hao|H|', 'Zhang|Ping|P|', 'Sun|Jin-Tang|JT|', 'Li|Gang|G|']
D000818:Animals D017209:Apoptosis D051017:Apoptosis Regulatory Proteins D001343:Autophagy D000071186:Beclin-1 D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D002738:Chloroquine D004354:Drug Screening Assays, Antitumor D005260:Female D005909:Glioblastoma D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D051379:Mice D008807:Mice, Inbred BALB C D009368:Neoplasm Transplantation D010936:Plant Extracts D019253:Proto-Oncogene Proteins c-bcl-2 D034741:RNA, Small Interfering D015398:Signal Transduction D014162:Transfection D014315:Triterpenes
Cucurbitacin I Autophagy Glioblastoma Apoptosis Chloroquine Hypoxia-inducible Factor (HIF) Signal Transduction