Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics
Abstract: Glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. We investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. High anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein-targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3-mimetics
- Standort
-
Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
-
Englisch
- Anmerkungen
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Cell death and differentiation. - 29, 10 (2022) , 2089-2104, ISSN: 1476-5403
- Ereignis
-
Veröffentlichung
- (wo)
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Freiburg
- (wer)
-
Universität
- (wann)
-
2022
- Urheber
- DOI
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10.1038/s41418-022-01001-3
- URN
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urn:nbn:de:bsz:25-freidok-2266972
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
- 15.08.2025, 07:20 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Koessinger, Anna L.
- Kössinger, Dominik
- Heiland, Dieter Henrik
- Schnell, Oliver
- Tait, Stephen W. G.
- Universität
Entstanden
- 2022
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