title: The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma.
abstract: 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.
authors.affiliation: Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy.|Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Cristofori
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.|Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy.|Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bertolini
authors.affiliation: Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy.|Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gaudioso
authors.affiliation: Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy.|Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Maria Veronica
authors.initials: MV
authors.lastname: Russo
authors.affiliation: Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Berno
authors.affiliation: Surgical Pathology Unit, St. Anna Hospital, Como, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vanini
authors.affiliation: Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Locatelli
authors.affiliation: Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy.|Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Zavanone
authors.affiliation: Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rampini
authors.affiliation: IFOM - The FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vaccari
authors.affiliation: Division of Neurosurgery, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Caroli
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.|Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D002470:Cell Survival; D005260:Female; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D034741:RNA, Small Interfering; D025262:Vacuolar Proton-Translocating ATPases
keywords: bafilomycin A1; cancer stem cells; glioblastoma; organotypic tissue cultures; vacuolar H+-ATPase