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BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery

Oncogene volume 32, pages 4748–4757 (2013)Cite this article

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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.

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Acknowledgements

We thank Dr Martin Hermann und Dr Albert Amberger (Medical University Innsbruck) for valuable discussion. This work was supported by the COMET Center ONCOTYROL, which is funded by the Austrian Federal Ministries BMVIT/BMWFJ (via FFG) and the Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT) and by grants from ‘Kinderkrebshilfe Tirol und Vorarlberg’, the ‘Krebshilfe Südtirol’, the ‘SVP-Frauen-Initiative’, the ‘Kinderkrebshilfe Südtirol-Regenbogen’, the Austrian Science Fund (P22080-B20), by the intramural funding program of the Medical University Innsbruck for young scientists MUI-START (P2012032014) and by the OeNB Anniversary Fund (P12582). The Tyrolean Cancer Research Institute and this study are supported by the ‘Tiroler Landeskrankenanstalten Ges.m.b.H. (TILAK)’ and the ‘Tyrolean Cancer Society’.

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Authors and Affiliations

  1. Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria

    J Hagenbuchner & P Obexer

  2. Tyrolean Cancer Research Institute, Innsbruck, Austria

    J Hagenbuchner, P Obexer & M J Ausserlechner

  3. Department of Cardiac Surgery, Cardiac Surgery Research Laboratory, Medical University Innsbruck, Innsbruck, Austria

    A V Kuznetsov

  4. Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria

    M J Ausserlechner

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  1. J Hagenbuchner
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Correspondence to P Obexer or M J Ausserlechner.

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Hagenbuchner, J., Kuznetsov, A., Obexer, P. et al. BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene 32, 4748–4757 (2013). https://doi.org/10.1038/onc.2012.500

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