Mitochondrial survivin - an Achilles' heel in cancer chemoresistance

Abstract

The metabolic shift from oxidative phosphorylation to glycolysis as a hallmark of highly aggressive cancer was postulated by Otto Warburg in the 1920s. We identified baculoviral IAP repeat-containing 5 (BIRC5, also known as survivin) as a key player in mitochondrial metabolism and our recent findings suggest glycolysis inhibitors as powerful agents to overcome the antiapoptotic function of survivin in neuroblastoma.

Keywords: Autophagy; Warburg effect; glycolysis inhibitors; mitochondria; neuroblastoma.

Figure 1.

Mitochondrial survivin and glycolysis-inhibition by 2-deoxy-D-glucose (2DG) in neuroblastoma. Increased expression of endogenous survivin causes mitochondrial fission via recruitment of the fission protein Drp1. In such cells mitochondrial survivin interacts with parkin and beclin-1, forming a hypothetical “survivosome” complex. 2DG treatment induces PINK and subsequent phosphorylation/activation of parkin and degradation of survivin, and thereby triggers the formation of mitochondrial networks. The release of beclin-1 from survivin further promotes autophagy-related survivin degradation, autophagosome formation, and autophagic flux, as visualized with a tandem DSRED-LC3-GFP protein. 2DG, 2-deoxy-D-glucose; Drp1, dynamin-like-protein1; GFP, green fluorescent protein; LC3, microtubule-associated protein 1 light chain 3 α (MAP1LC3A); parkin, parkin RBR E3 ubiquitin protein ligase; PINK, PTEN-induced kinase; u, ubiquitin.