title: Potential therapeutic target for malignant paragangliomas: ATP synthase on the surface of paraganglioma cells.
abstract: F1FoATP synthase (ATP synthase) is a ubiquitous enzyme complex in eukaryotes. In general it is localized to the mitochondrial inner membrane and serves as the last step in the mitochondrial oxidative phosphorylation of ADP to ATP, utilizing a proton gradient across the inner mitochondrial membrane built by the complexes of the electron transfer chain. However some cell types, including tumors, carry ATP synthase on the cell surface. It was suggested that cell surface ATP synthase helps tumor cells thriving on glycolysis to survive their high acid generation. Angiostatin, aurovertin, resveratrol, and antibodies against the α and β subunits of ATP synthase were shown to bind and selectively inhibit cell surface ATP synthase, promoting tumor cell death. Here we show that ATP synthase β (ATP5B) is present on the cell surface of mouse pheochromocytoma cells as well as tumor cells of human SDHB-derived paragangliomas (PGLs), while being virtually absent on chromaffin primary cells from bovine adrenal medulla by confocal microscopy. The cell surface location of ATP5B was verified in the tissue of an SDHB-derived PGL by immunoelectron microscopy. Treatment of mouse pheochromocytoma cells with resveratrol as well as ATP5B antibody led to statistically significant proliferation inhibition. Our data suggest that PGLs carry ATP synthase on their surface that promotes cell survival or proliferation. Thus, cell surface ATP synthase may present a novel therapeutic target in treating metastatic or inoperable PGLs.
authors.affiliation: Program on Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Bethesda, MD 20892, USA ; 1st Department of Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: Stephanie Mj
authors.initials: SM
authors.lastname: Fliedner
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda, MD 20892, USA.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.affiliation: Program on Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Bethesda, MD 20892, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Thompson
authors.affiliation: Section of Immunopathology, National Eye Institute, NIH, National Institutes of Health Bethesda, MD 20892, USA.
authors.forename: Mones
authors.initials: M
authors.lastname: Abu-Asab
authors.affiliation: Section on Molecular Neuroscience, National Institute of Mental Health, National Institutes of Health Bethesda, Maryland 20892, USA.
authors.forename: Chang-Mei
authors.initials: CM
authors.lastname: Hsu
authors.affiliation: No affiliation.
authors.forename: Gary
authors.initials: G
authors.lastname: Lampert
authors.affiliation: Section on Molecular Neuroscience, National Institute of Mental Health, National Institutes of Health Bethesda, Maryland 20892, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Eiden
authors.affiliation: Department of Pathology and Laboratory Medicine, Tufts Medical Center Boston, MA 02111, USA.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Tischler
authors.affiliation: Department of Health and Human Services, Clinical Center, National Institutes of Health Bethesda, MD 20892, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wesley
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda, MD 20892, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: 1st Department of Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.affiliation: Program on Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Bethesda, MD 20892, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
keywords: Cell surface ATP synthase; mouse pheochromocytoma cells; paraganglioma; pheochromocytoma; resveratrol