Please use this identifier to cite or link to this item: doi:10.22028/D291-39757
Title: 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
Author(s): 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.
Language: English
Title: Cells
Volume: 12
Issue: 9
Publisher/Platform: MDPI
Year of Publication: 2023
Free key words: chloroquine
glioblastoma radiosensitization
glioblastoma stem cells
DDC notations: 610 Medicine and health
Publikation type: Journal Article
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 of the first publication: 10.3390/cells12091290
URL of the first publication:
Link to this record: urn:nbn:de:bsz:291--ds-397576
ISSN: 2073-4409
Date of registration: 16-May-2023
Description of the related object: Supplementary Materials
Related object:
Faculty: M - Medizinische Fakultät
Department: M - Neuropathologie
Professorship: M - Prof. Dr. Walter Schulz-Schaeffer
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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