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.
Highlights
Neuroblastoma is a pediatric malignancy that develops from undifferentiated precursors of the sympathetic nervous system
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
Anti-mitotic drugs have been used for a long time in cancer therapy but, as true for almost all other chemotherapeutics, their therapeutic efficacy is challenged by cancer cells that develop drug resistance
Summary
Neuroblastoma is a pediatric malignancy that develops from undifferentiated precursors of the sympathetic nervous system. Anti-mitotic drugs have been used for treating a variety of malignancies These compounds are frequently of natural origin and possess high antiproliferative effects [7]. There are two major classes of compounds which interfere with microtubule dynamics: Inhibitors of the tubulin assembly into microtubule structures or the inhibitors of microtubule disassembly In principal, they can bind to three different sites of tubulin, the paclitaxel site, the vinca-domain or into the colchicine site [8]. Since cancer cells are fast dividing cells, improvement of these substances is still of high scientific interest to overcome resistance Understanding their modes of action might improve combination therapies and reduce effective doses. Antimitotic drugs possess high cytotoxic potential, since they target a large number of signaling pathways and proteins and many reports suggest the involvement of autophagy related genes as well as members of the BCL2 family [10, 11]
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