The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma
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Andrea Di Cristofori1,2,*, Stefano Ferrero3,4,*, Irene Bertolini1,3, Gabriella Gaudioso1,3, Maria Veronica Russo1,3, Valeria Berno5, Marco Vanini6, Marco Locatelli2, Mario Zavanone1,2, Paolo Rampini2, Thomas Vaccari7, Manuela Caroli2 and Valentina Vaira3,5
1 Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy
2 Division of Neurosurgery, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
3 Division of Pathology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
4 Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
5 Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milan, Italy
6 Surgical Pathology Unit, St. Anna Hospital, Como, Italy
7 IFOM - The FIRC Institute of Molecular Oncology, Milan, Italy
* These authors have equally contributed to this work
Manuela Caroli, email:
Valentina Vaira, email:
Keywords: glioblastoma, vacuolar H+-ATPase, bafilomycin A1, cancer stem cells, organotypic tissue cultures
Received: January 16, 2015 Accepted: May 02, 2015 Published: May 22, 2015
The vacuolar H+ ATPase (V-ATPase) is a proton pump responsible for acidification of cellular microenvironments, an activity exploited by tumors to survive, proliferate and resist to therapy. Despite few observations, the role of V-ATPase in human tumorigenesis remains unclear.
We investigated the expression of ATP6V0C, ATP6V0A2, encoding two subunits belonging to the V-ATPase V0 sector and ATP6V1C, ATP6V1G1, ATPT6V1G2, ATP6V1G3, which are part of the V1 sector, in series of adult gliomas and in cancer stem cell-enriched neurospheres isolated from glioblastoma (GBM) patients. ATP6V1G1 expression resulted significantly upregulated in tissues of patients with GBM and correlated with shorter patients’ overall survival independent of clinical variables.
ATP6V1G1 knockdown in GBM neurospheres hampered sphere-forming ability, induced cell death, and decreased matrix invasion, a phenotype not observed in GBM monolayer cultures. Treating GBM organotypic cultures or neurospheres with the selective V-ATPase inhibitor bafilomycin A1 reproduced the effects of ATP6V1G1 siRNA and strongly suppressed expression of the stem cell markers Nestin, CD133 and transcription factors SALL2 and POU3F2 in neurospheres.
These data point to ATP6V1G1 as a novel marker of poor prognosis in GBM patients and identify V-ATPase inhibition as an innovative therapeutic strategy for GBM.
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