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...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
27 October 2024
|
| In: |
Molecular oncology
Year: 2025, Jahrgang: 19, Heft: 3, Pages: 785-807 |
| ISSN: | 1878-0261 |
| DOI: | 10.1002/1878-0261.13756 |
| Online-Zugang: | 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 
|
| Verfasserangaben: | 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 |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1923883194 | ||
| 003 | DE-627 | ||
| 005 | 20250717012209.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 250429s2025 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/1878-0261.13756 |2 doi | |
| 035 | |a (DE-627)1923883194 | ||
| 035 | |a (DE-599)KXP1923883194 | ||
| 035 | |a (OCoLC)1528045016 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Phillips, Emma |e VerfasserIn |0 (DE-588)111330667X |0 (DE-627)867175109 |0 (DE-576)476950570 |4 aut | |
| 245 | 1 | 0 | |a Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade |c 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 |
| 264 | 1 | |c 27 October 2024 | |
| 300 | |b Illustrationen | ||
| 300 | |a 23 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 29.04.2025 | ||
| 520 | |a 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. | ||
| 650 | 4 | |a Animals | |
| 650 | 4 | |a autophagy | |
| 650 | 4 | |a Autophagy | |
| 650 | 4 | |a Brain Neoplasms | |
| 650 | 4 | |a cancer | |
| 650 | 4 | |a Cell Line, Tumor | |
| 650 | 4 | |a compound screen | |
| 650 | 4 | |a glioblastoma | |
| 650 | 4 | |a Glioblastoma | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a Mice | |
| 650 | 4 | |a Neoplastic Stem Cells | |
| 650 | 4 | |a proteostasis | |
| 650 | 4 | |a Proteotoxic Stress | |
| 650 | 4 | |a stem cells | |
| 650 | 4 | |a unfolded protein response | |
| 650 | 4 | |a Unfolded Protein Response | |
| 650 | 4 | |a Xenograft Model Antitumor Assays | |
| 700 | 1 | |a van Enk, Sizèd |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kildgaard, Sara |e VerfasserIn |4 aut | |
| 700 | 1 | |a Schlue, Silja |e VerfasserIn |4 aut | |
| 700 | 1 | |a Göttmann, Mona |e VerfasserIn |4 aut | |
| 700 | 1 | |a Jennings, Victoria |e VerfasserIn |4 aut | |
| 700 | 1 | |a Bethke, Frederic |e VerfasserIn |4 aut | |
| 700 | 1 | |a Müller, Gabriele |e VerfasserIn |4 aut | |
| 700 | 1 | |a Herold-Mende, Christel |e VerfasserIn |0 (DE-588)1022936549 |0 (DE-627)717335577 |0 (DE-576)366194267 |4 aut | |
| 700 | 1 | |a Pastor-Flores, Daniel |e VerfasserIn |4 aut | |
| 700 | 1 | |a Schneider, Martin |e VerfasserIn |4 aut | |
| 700 | 1 | |a Helm, Dominic |e VerfasserIn |0 (DE-588)1261933672 |0 (DE-627)1809321239 |4 aut | |
| 700 | 1 | |a Ostenfeld Larsen, Thomas |e VerfasserIn |4 aut | |
| 700 | 1 | |a Goidts, Violaine |d 1981- |e VerfasserIn |0 (DE-588)132073714 |0 (DE-627)517467585 |0 (DE-576)255439474 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular oncology |d Hoboken, NJ : John Wiley & Sons, Inc., 2007 |g 19(2025), 3, Seite 785-807 |h Online-Ressource |w (DE-627)531199800 |w (DE-600)2322586-5 |w (DE-576)271586621 |x 1878-0261 |7 nnas |a Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| 773 | 1 | 8 | |g volume:19 |g year:2025 |g number:3 |g pages:785-807 |g extent:23 |a Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade |
| 856 | 4 | 0 | |u https://doi.org/10.1002/1878-0261.13756 |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |
| 856 | 4 | 0 | |u https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.13756 |x Resolving-System |z kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20250429 | ||
| 993 | |a Article | ||
| 994 | |a 2025 | ||
| 998 | |g 132073714 |a Rosenstiel-Goidts, Violaine |m 132073714:Rosenstiel-Goidts, Violaine |d 140000 |e 140000PR132073714 |k 0/140000/ |p 14 |y j | ||
| 998 | |g 1261933672 |a Helm, Dominic |m 1261933672:Helm, Dominic |d 50000 |e 50000PH1261933672 |k 0/50000/ |p 12 | ||
| 998 | |g 1022936549 |a Herold-Mende, Christel |m 1022936549:Herold-Mende, Christel |d 910000 |d 911200 |e 910000PH1022936549 |e 911200PH1022936549 |k 0/910000/ |k 1/910000/911200/ |p 9 | ||
| 999 | |a KXP-PPN1923883194 |e 4715814730 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"language":["eng"],"note":["Gesehen am 29.04.2025"],"person":[{"display":"Phillips, Emma","family":"Phillips","role":"aut","given":"Emma"},{"given":"Sizèd","display":"van Enk, Sizèd","role":"aut","family":"van Enk"},{"given":"Sara","family":"Kildgaard","role":"aut","display":"Kildgaard, Sara"},{"given":"Silja","role":"aut","family":"Schlue","display":"Schlue, Silja"},{"display":"Göttmann, Mona","family":"Göttmann","role":"aut","given":"Mona"},{"display":"Jennings, Victoria","family":"Jennings","role":"aut","given":"Victoria"},{"given":"Frederic","display":"Bethke, Frederic","family":"Bethke","role":"aut"},{"family":"Müller","role":"aut","display":"Müller, Gabriele","given":"Gabriele"},{"given":"Christel","role":"aut","family":"Herold-Mende","display":"Herold-Mende, Christel"},{"family":"Pastor-Flores","role":"aut","display":"Pastor-Flores, Daniel","given":"Daniel"},{"given":"Martin","display":"Schneider, Martin","family":"Schneider","role":"aut"},{"display":"Helm, Dominic","family":"Helm","role":"aut","given":"Dominic"},{"display":"Ostenfeld Larsen, Thomas","role":"aut","family":"Ostenfeld Larsen","given":"Thomas"},{"family":"Goidts","role":"aut","display":"Goidts, Violaine","given":"Violaine"}],"type":{"media":"Online-Ressource","bibl":"article-journal"},"id":{"eki":["1923883194"],"doi":["10.1002/1878-0261.13756"]},"recId":"1923883194","origin":[{"dateIssuedDisp":"27 October 2024","dateIssuedKey":"2025"}],"name":{"displayForm":["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"]},"relHost":[{"disp":"Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockadeMolecular oncology","origin":[{"dateIssuedDisp":"2007-","publisherPlace":"Hoboken, NJ ; Amsterdam [u.a.]","dateIssuedKey":"2007","publisher":"John Wiley & Sons, Inc. ; Elsevier"}],"name":{"displayForm":["Federation of European Biochemical Societies"]},"recId":"531199800","id":{"eki":["531199800"],"zdb":["2322586-5"],"issn":["1878-0261"]},"type":{"media":"Online-Ressource","bibl":"periodical"},"pubHistory":["1.2007 -"],"note":["Gesehen am 25.06.20"],"language":["eng"],"part":{"extent":"23","issue":"3","year":"2025","pages":"785-807","volume":"19","text":"19(2025), 3, Seite 785-807"},"physDesc":[{"extent":"Online-Ressource"}],"title":[{"title_sort":"Molecular oncology","title":"Molecular oncology"}]}],"title":[{"title_sort":"Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade","title":"Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade"}],"physDesc":[{"extent":"23 S.","noteIll":"Illustrationen"}]} | ||
| SRT | |a PHILLIPSEMMALFORMINC2720 | ||