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Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade

Glioblastoma is a highly aggressive brain tumor for which there is no cure. The dire prognosis of this disease is largely attributable to a high level of heterogeneity, including the presence of a subpopulation of tumor-initiating glioblastoma stem-like cells (GSCs), which are refractory to chemo- a...

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Main Authors: Phillips, Emma (Author) , van Enk, Sizèd (Author) , Kildgaard, Sara (Author) , Schlue, Silja (Author) , Göttmann, Mona (Author) , Jennings, Victoria (Author) , Bethke, Frederic (Author) , Müller, Gabriele (Author) , Herold-Mende, Christel (Author) , Pastor-Flores, Daniel (Author) , Schneider, Martin (Author) , Helm, Dominic (Author) , Ostenfeld Larsen, Thomas (Author) , Goidts, Violaine (Author)
Format: Article (Journal)
Language:English
Published: 27 October 2024
In: Molecular oncology
Year: 2025, Volume: 19, Issue: 3, Pages: 785-807
ISSN:1878-0261
DOI:10.1002/1878-0261.13756
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/1878-0261.13756
Resolving-System, kostenfrei, Volltext: https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.13756
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Author Notes:Emma Phillips, Sizèd van Enk, Sara Kildgaard, Silja Schlue, Mona Göttmann, Victoria Jennings, Frederic Bethke, Gabriele Müller, Christel Herold-Mende, Daniel Pastor-Flores, Martin Schneider, Dominic Helm, Thomas Ostenfeld Larsen, Violaine Goidts
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Summary:Glioblastoma is a highly aggressive brain tumor for which there is no cure. The dire prognosis of this disease is largely attributable to a high level of heterogeneity, including the presence of a subpopulation of tumor-initiating glioblastoma stem-like cells (GSCs), which are refractory to chemo- and radiotherapy. Here, in an unbiased marine-derived fungal extract screen, together with bioguided dereplication based on high-resolution mass spectrometry, we identified malformin C to preferentially induce cell death in patient-derived GSCs and explore the potential of this cyclic peptide as a therapeutic agent for glioblastoma. Malformin C significantly reduced tumor growth in an in vivo xenograft model of glioblastoma. Using transcriptomics and chemoproteomics, we found that malformin C binds to many proteins, leading to their aggregation, and rapidly induces the unfolded protein response, including autophagy, in GSCs. Crucially, chemical inhibition of translation using cycloheximide rescued malformin C-induced cell death in GSCs, demonstrating that the proteotoxic effect of the compound is necessary for its cytotoxicity. At the same time, malformin C appears to accumulate in lysosomes, disrupting autophagic flux, and driving cells to death. Supporting this, malformin C synergizes with chloroquine, an inhibitor of autophagy. Strikingly, we observed that autophagic flux is differentially regulated in GSCs compared with normal astrocytes. The sensitivity of GSCs to malformin C highlights the relevance of proteostasis and autophagy as a therapeutic vulnerability in glioblastoma.
Item Description:Gesehen am 29.04.2025
Physical Description:Online Resource
ISSN:1878-0261
DOI:10.1002/1878-0261.13756

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