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BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma

Abstract

Adverse forms of neuroblastoma (NB), a childhood malignancy that develops from immature neuronal progenitor cells frequently carry a gain of chromosome 17q, which leads to overexpression of the antiapoptotic protein BIRC5/Survivin. We have recently shown that high Survivin expression shuts down mitochondrial complex I activity and shifts NB cells from oxidative phosphorylation to aerobic glycolysis, which further increases resistance to cell death induction. This increased glucose consumption sensitized tumor cells to glycolysis inhibitors. Interestingly, in Survivin-overexpressing cells 2-deoxy-d-glucose (2DG) treatment induces re-fusion of mitochondrial networks after 4 h, which coincides with Survivin repression. 2DG selectively acts on Survivin-expressing NB cells and induces autophagic degradation of Survivin via activation of the E3-ubiquitin ligase Parkin, a downstream target of PINK1. Survivin degradation further releases bound Beclin-1, which enhances autophagy and cell death induction. Knockdown of Parkin, however, reduces the sensitivity of Survivin-expressing NB cells to glycolysis inhibition. The selective activity of 2DG treatment on Survivin-overexpressing tumor cells was also confirmed in a xenograft mouse model, which further supports our hypothesis that glycolysis inhibitors might be useful drugs in the treatment of NB.

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Acknowledgements

We thank Dr Hermann Dietrich and his team for the animal care. This work was supported by the intramural funding program of the Medical University Innsbruck for young scientists MUI-START (P2012032014) and by grants from the ‘Provita Kinderleukämie Stiftung’, the ‘Medizinische Forschungsfond Tirol’ and ‘SVP-Frauen-Initiative’. This study is supported by the ‘Tiroler Landeskrankenanstalten Ges.m.b.H. (TILAK)’ and the ‘Tyrolean Cancer Society’.

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Hagenbuchner, J., Kiechl-Kohlendorfer, U., Obexer, P. et al. BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma. Oncogene 35, 2052–2061 (2016). https://doi.org/10.1038/onc.2015.264

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