title: BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery.
abstract: Gain of chromosome 17q correlates with high-stage disease, an adverse clinical outcome and leads to the overexpression of the antiapoptotic protein BIRC5/Survivin in neuroblastoma (NB). We have shown before that Survivin defines a threshold for the sensitivity of NB cells to DNA-damaging chemotherapeutic agents that require FOXO3 activation for apoptosis induction. To investigate the molecular basis of apoptosis inhibition we analyzed the function of Survivin at mitochondria and uncovered that Survivin induces mitochondrial fragmentation, reduces mitochondrial respiration and represses BCL2L11/Bim. Mitochondrial fission depends on Survivin-induced recruitment of the fission regulator DNM1L/Drp1 to mitochondria. In parallel, Survivin expression inhibits the respiratory complex-I, thereby preventing reactive oxygen species accumulation and, as a consequence, FOXO3-induced apoptosis. The loss of energy production via oxidative phosphorylation is compensated by increased glycolysis in Survivin-overexpressing NB tumor cells. Glycolysis inhibitors neutralize the antiapoptotic effect of Survivin and sensitize high-stage NB to DNA-damaging drugs. This suggests that glycolysis inhibitors target an 'archilles heel' of Survivin-overexpressing NB and may be highly useful as chemosensitizers in the treatment of high-stage NB.
authors.affiliation: 1] Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria [2] Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Hagenbuchner
authors.forename: A V
authors.initials: AV
authors.lastname: Kuznetsov
authors.forename: P
authors.initials: P
authors.lastname: Obexer
authors.forename: M J
authors.initials: MJ
authors.lastname: Ausserlechner
mesh_terms: D000332:Aerobiosis; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology*; D034281:Dynamins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C107489:BIRC5 protein, human; D000072224:Bcl-2-Like Protein 11; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins