Abstract
There is an urgent need for new therapeutic strategies for patients with glioblastoma multiforme (GBM). Previous studies have shown that berberine (BBR), a natural plant alkaloid, has potent anti-tumor activity. However, the mechanisms leading to cancer cell death have not been clearly elucidated. In this study, we show that BBR has profound effects on the metabolic state of GBM cells, leading to high autophagy flux and impaired glycolytic capacity. Functionally, these alterations reduce the invasive properties, proliferative potential and induce apoptotic cell death. The molecular alterations preceding these changes are characterized by inhibition of the AMPK/mTOR/ULK1 pathway. Finally, we demonstrate that BBR significantly reduces tumor growth in vivo, demonstrating the potential clinical benefits for autophagy modulating plant alkaloids in cancer therapy.
Keywords:
apoptosis; autophagy; berberine; glioblastoma; metabolism.
MeSH terms
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AMP-Activated Protein Kinases / drug effects
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AMP-Activated Protein Kinases / metabolism
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology*
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Autophagy / drug effects*
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Autophagy-Related Protein-1 Homolog / drug effects
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Autophagy-Related Protein-1 Homolog / metabolism
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Berberine / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Glioblastoma / metabolism
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Glioblastoma / pathology*
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Humans
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Intracellular Signaling Peptides and Proteins / drug effects
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Nude
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / drug effects
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TOR Serine-Threonine Kinases / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Phytogenic
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Intracellular Signaling Peptides and Proteins
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Berberine
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MTOR protein, human
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Autophagy-Related Protein-1 Homolog
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TOR Serine-Threonine Kinases
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ULK1 protein, human
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AMP-Activated Protein Kinases