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Titel: Concurrent Activation of Both Survival-Promoting and Death-Inducing Signaling by Chloroquine in Glioblastoma Stem Cells : Implications for Potential Risks and Benefits of Using Chloroquine as Radiosensitizer
VerfasserIn: Müller, Andreas
Weyerhäuser, Patrick
Berte, Nancy
Jonin, Fitriasari
Lyubarskyy, Bogdan
Sprang, Bettina
Kantelhardt, Sven Rainer
Salinas, Gabriela
Opitz, Lennart
Schulz-Schaeffer, Walter
Giese, Alf
Kim, Ella L.
Sprache: Englisch
Titel: Cells
Bandnummer: 12
Heft: 9
Verlag/Plattform: MDPI
Erscheinungsjahr: 2023
Freie Schlagwörter: chloroquine
glioblastoma radiosensitization
glioblastoma stem cells
p53
p21-DREAM
ATM
AKT
HIPK2
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Lysosomotropic agent chloroquine was shown to sensitize non-stem glioblastoma cells to radiation in vitro with p53-dependent apoptosis implicated as one of the underlying mechanisms. The in vivo outcomes of chloroquine or its effects on glioblastoma stem cells have not been previously addressed. This study undertakes a combinatorial approach encompassing in vitro, in vivo and in silico investigations to address the relationship between chloroquine-mediated radiosensitization and p53 status in glioblastoma stem cells. Our findings reveal that chloroquine elicits antagonistic impacts on signaling pathways involved in the regulation of cell fate via both transcription-dependent and transcription-independent mechanisms. Evidence is provided that transcriptional impacts of chloroquine are primarily determined by p53 with chloroquine-mediated activation of pro-survival mevalonate and p21-DREAM pathways being the dominant response in the background of wild type p53. Non-transcriptional effects of chloroquine are conserved and converge on key cell fate regulators ATM, HIPK2 and AKT in glioblastoma stem cells irrespective of their p53 status. Our findings indicate that pro-survival responses elicited by chloroquine predominate in the context of wild type p53 and are diminished in cells with transcriptionally impaired p53. We conclude that p53 is an important determinant of the balance between pro-survival and pro-death impacts of chloroquine and propose that p53 functional status should be taken into consideration when evaluating the efficacy of glioblastoma radiosensitization by chloroquine.
DOI der Erstveröffentlichung: 10.3390/cells12091290
URL der Erstveröffentlichung: https://doi.org/10.3390/cells12091290
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-397576
hdl:20.500.11880/35839
http://dx.doi.org/10.22028/D291-39757
ISSN: 2073-4409
Datum des Eintrags: 16-Mai-2023
Bezeichnung des in Beziehung stehenden Objekts: Supplementary Materials
In Beziehung stehendes Objekt: http://www.mdpi.com/article/10.3390/cells12091290/s1
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Neuropathologie
Professur: M - Prof. Dr. Walter Schulz-Schaeffer
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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