Hagenbuchner 2013 Oncogene

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Publications in the MiPMap
Hagenbuchner J, Kuznetsov AV, Obexer P, Ausserlechner MJ (2013) BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene 32:4748-57.

» PMID: 23146905

Hagenbuchner J, Kuznetsov AV, Obexer P, Ausserlechner MJ (2013) Oncogene

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.

Keywords: Chemotherapy, FOXO3, Mitochondrial respiration, Reactive oxygen species, Warburg effect

Labels: MiParea: Respiration, mt-Structure;fission;fusion, Genetic knockout;overexpression 

Stress:Cell death  Organism: Human  Tissue;cell: Other cell lines  Preparation: Intact cells, Permeabilized cells 

Coupling state: OXPHOS, ET  Pathway: N, S, CIV  HRR: Oxygraph-2k