Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

V-ATPase Proton Pump May Take Part to Drug-Resistance Phenotype of Glioma Stem Cells

Martina Giambra
ORCID logo ,
Andrea Di Cristofori
* ,
Francesca Raimondo
ORCID logo ,
Roberta Rigolio
,
Donatella Conconi
ORCID logo ,
Gaia Chiarello
,
Silvia Maria Tabano
ORCID logo ,
Laura Antolini
,
Gabriella Nicolini
ORCID logo ,
Miriam Bua
,
Davide Ferlito
ORCID logo ,
Giorgio Carrabba
ORCID logo ,
Carlo Giorgio Giussani
ORCID logo ,
Marialuisa Lavitrano
ORCID logo ,
Angela Bentivegna
* ORCID logo
Version 1 : Received: 1 February 2024 / Approved: 1 February 2024 / Online: 1 February 2024 (12:06:35 CET)

A peer-reviewed article of this Preprint also exists.

Giambra, M.; Di Cristofori, A.; Raimondo, F.; Rigolio, R.; Conconi, D.; Chiarello, G.; Tabano, S.M.; Antolini, L.; Nicolini, G.; Bua, M.; Ferlito, D.; Carrabba, G.; Giussani, C.G.; Lavitrano, M.; Bentivegna, A. Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells. Int. J. Mol. Sci. 2024, 25, 2743. Giambra, M.; Di Cristofori, A.; Raimondo, F.; Rigolio, R.; Conconi, D.; Chiarello, G.; Tabano, S.M.; Antolini, L.; Nicolini, G.; Bua, M.; Ferlito, D.; Carrabba, G.; Giussani, C.G.; Lavitrano, M.; Bentivegna, A. Vacuolar Proton-Translocating ATPase May Take Part in the Drug Resistance Phenotype of Glioma Stem Cells. Int. J. Mol. Sci. 2024, 25, 2743.

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 is mainly based on anaerobic glycolytic reactions. Moreover, the neoplastic cells use the V-ATPase to extrude chemotherapy drugs to 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 patients-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome the resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 lead to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models that are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem component, encouraging the search for novel strategies to limit its activity in order to get around the resistance to the conventional therapy.

Keywords

glioblastoma; GBM; glioma stem cells; GSCs; chemoresistance; V-ATPase; bafilomycin A1; temozolomide; autophagy process

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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