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Cucurbitacin I induces protective autophagy in glioblastoma in vitro and in vivo.

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.
AuthorsGuang Yuan, Shao-Feng Yan, Hao Xue, Ping Zhang, Jin-Tang Sun, Gang Li
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 15 Pg. 10607-10619 (Apr 11 2014) ISSN: 1083-351X [Electronic] United States
PMID24599950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Plant Extracts
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Triterpenes
  • Chloroquine
  • cucurbitacin I
Topics
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins (metabolism)
  • Autophagy (drug effects)
  • Beclin-1
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Chloroquine (pharmacology)
  • Drug Screening Assays, Antitumor
  • Female
  • Glioblastoma (drug therapy, metabolism)
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Plant Extracts (pharmacology)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • RNA, Small Interfering (metabolism)
  • Signal Transduction
  • Transfection
  • Triterpenes (pharmacology, therapeutic use)

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