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Oncotarget. 2017 Mar 22. doi: 10.18632/oncotarget.16434. [Epub ahead of print]

The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma.

Author information

1
Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria.
2
Tyrolean Cancer Research Institute, Innsbruck, Austria.
3
Department of Woman's and Child's Health, Oncohematology Laboratory University of Padova, Padova, Italy.
4
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
5
Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria.

Abstract

Neuroblastoma is the most frequent extra-cranial solid tumor in children with still high mortality in stage M. Here we studied the tubulin-inhibitor MG-2477 as a possible therapeutic agent for neuroblastoma therapy and uncovered that MG-2477 induces death in neuroblastoma cells independent of PKB-activation status and stage. MG-2477 triggers within 30 minutes extensive autophagosome-formation that finally leads to cell death associated with mitotic catastrophe. Autophagy is critical for MG-2477-induced death and is regulated by the BH3-only protein PMAIP1/NOXA which sequesters the anti-apoptotic BCL2-protein BCLXL and thereby displaces and activates the autophagy-regulator BECN1/beclin1. Knockdown of NOXA or overexpression of its pro-survival binding partners MCL1 and BCLXL counteracts MG-2477-induced cell death. MG-2477 also rapidly induces the repression of the anti-apoptotic protein Survivin, which promotes autophagy and cell death. We further observed the accumulation of reactive oxygen species (ROS) that triggers autophagy induction suggesting a change of the PI3 kinase-III/BECN1 complex and activates the transcription factor FOXO3, which contributes to final cell death induction. The combined data suggest that MG-2477 induces a sequential process of ROS-accumulation, autophagy and FOXO3-activation that leads to cell death in neuroblastoma cells.

KEYWORDS:

BCLXL; BIRC5/Survivin; NOXA; Tubulin-inhibition; autophagy

PMID:
28415610
DOI:
10.18632/oncotarget.16434
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