The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy.

Giambra, M., Di Cristofori, A., Raimondo, F., Rigolio, R., Conconi, D., Chiarello, G., et al. (2024). Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 25(5) [10.3390/ijms25052743].

Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells

Giambra, Martina
Primo
;
Di Cristofori, Andrea
Secondo
;
Raimondo, Francesca;Rigolio, Roberta;Conconi, Donatella;Antolini, Laura;Nicolini, Gabriella
;
Bua, Miriam;Ferlito, Davide;Carrabba, Giorgio;Giussani, Carlo Giorgio;Lavitrano, Marialuisa
Penultimo
;
Bentivegna, Angela
Ultimo
2024

Abstract

The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy.
Articolo in rivista - Articolo scientifico
autophagy process; bafilomycin A1; chemoresistance; GBM; glioblastoma; glioma stem cells; GSCs; temozolomide; V-ATPase;
English
27-feb-2024
2024
25
5
2743
open
Giambra, M., Di Cristofori, A., Raimondo, F., Rigolio, R., Conconi, D., Chiarello, G., et al. (2024). Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 25(5) [10.3390/ijms25052743].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/462084
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