Cucurbitacin I Induces Protective Autophagy in Glioblastoma in Vitro and in Vivo |
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Authors: | Guang Yuan Shao-Feng Yan Hao Xue Ping Zhang Jin-Tang Sun Gang Li |
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Institution: | From the ‡Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, China.;the §Brain Science Research Institute, Shandong University, 44 Wenhua Xi Road, Jinan, China, and ;the ¶Institute of Basic Medical Sciences and Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, 44 Wenhua Xi Road, Jinan, China |
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Abstract: | 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. |
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Keywords: | Apoptosis Autophagy Glioblastoma Hypoxia-inducible Factor (HIF) Signal Transduction Chloroquine Cucurbitacin I |
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