title: Dual role of the mitochondrial protein frataxin in astrocytic tumors.
abstract: The mitochondrial protein frataxin (FXN) is known to be involved in mitochondrial iron homeostasis and iron-sulfur cluster biogenesis. It is discussed to modulate function of the electron transport chain and production of reactive oxygen species (ROS). FXN loss in neurons and heart muscle cells causes an autosomal-dominant mitochondrial disorder, Friedreich's ataxia. Recently, tumor induction after targeted FXN deletion in liver and reversal of the tumorigenic phenotype of colonic carcinoma cells following FXN overexpression were described in the literature, suggesting a tumor suppressor function. We hypothesized that a partial reversal of the malignant phenotype of glioma cells should occur after FXN transfection, if the mitochondrial protein has tumor suppressor functions in these brain tumors. In astrocytic brain tumors and tumor cell lines, we observed reduced FXN levels compared with non-neoplastic astrocytes. Mitochondrial content (citrate synthase activity) was not significantly altered in U87MG glioblastoma cells stably overexpressing FXN (U87-FXN). Surprisingly, U87-FXN cells exhibited increased cytoplasmic ROS levels, although mitochondrial ROS release was attenuated by FXN, as expected. Higher cytoplasmic ROS levels corresponded to reduced activities of glutathione peroxidase and catalase, and lower glutathione content. The defect of antioxidative capacity resulted in increased susceptibility of U87-FXN cells against oxidative stress induced by H(2)O(2) or buthionine sulfoximine. These characteristics may explain a higher sensitivity toward staurosporine and alkylating drugs, at least in part. On the other hand, U87-FXN cells exhibited enhanced growth rates in vitro under growth factor-restricted and hypoxic conditions and in vivo using tumor xenografts in nude mice. These data contrast to a general tumor suppressor function of FXN but suggest a dual, pro-proliferative but chemosensitizing role in astrocytic tumors.
authors.affiliation: Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Kirches
authors.forename: Nadine
authors.initials: N
authors.lastname: Andrae
authors.forename: Aline
authors.initials: A
authors.lastname: Hoefer
authors.forename: Barbara
authors.initials: B
authors.lastname: Kehler
authors.forename: Kim
authors.initials: K
authors.lastname: Zarse
authors.forename: Martin
authors.initials: M
authors.lastname: Leverkus
authors.forename: Gerburg
authors.initials: G
authors.lastname: Keilhoff
authors.forename: Peter
authors.initials: P
authors.lastname: Schonfeld
authors.forename: Thomas
authors.initials: T
authors.lastname: Schneider
authors.forename: Annette
authors.initials: A
authors.lastname: Wilisch-Neumann
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating; D017209:Apoptosis; D001254:Astrocytoma / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000096923:Frataxin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D033862:Iron-Binding Proteins; D017382:Reactive Oxygen Species; D000096923:Frataxin