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.