Cucurbitacin I Induces Protective Autophagy in Glioblastoma in vitro and in vivo [Cell Biology]

March 5th, 2014 by Yuan, G., Yan, S.-F., Xue, H., Zhang, P., Sun, J.-T., Li, G.

There is an urgent need for new therapeutic avenues to improve the outcome of patients with 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 upregulated Beclin 1 and triggered autophagosomes formation and accumulation, as well as conversion of LC3I to LC3II. Activation of the AMPK/mTOR/ p70S6K pathway, but not the PI3K/AKT pathway, occurred in autophagy induced by cucurbitacin I, which was accompanied by a decreased HIF-1α. Stable overexpression of a HIF-1α induced by FG-4497 prevented cucurbitacin I-induced autophagy and downregulation of bcl-2. Knockdown of beclin 1 or treatment with autophagy inhibitor 3-methyladenine also inhibited autophagy induced by cucurbitacin I. Co-immunoprecipitation assay showed the interaction of Bcl-2 and Beclin 1/hVps34 markedly decreased in cells treated with cucurbitacin I. Furthermore, knockdown of beclin 1 or treated with the lysosome inhibitor chloroquine sensitized cancer cells to cucurbitacin I-induced apoptosis. Finally, a xenograft model provided additional evidence for occurrence of cucurbitacin I-induced apoptosis and autophagy in vitro. Our findings provide new insights into the molecular mechanisms underlying cucurbitacin I-mediated GBM cells death and may comprise an efficacious therapy for patients harboring GBM.