The tubulin inhibitor MG-2477 induces autophagy-regulated cell death, ROS accumulation and activation of FOXO3 in neuroblastoma
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Judith Hagenbuchner1, Lorena Lungkofler3, Ursula Kiechl-Kohlendorfer1, Giampietro Viola4, Maria Grazia Ferlin5, Michael J. Ausserlechner2 and Petra Obexer1,3
1Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria
2Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria
3Tyrolean Cancer Research Institute, Innsbruck, Austria
4Department of Woman’s and Child’s Health, Oncohematology Laboratory University of Padova, Padova, Italy
5Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
Michael J. Ausserlechner, email: Michael.J.Ausserlechner@i-med.ac.at
Petra Obexer, email: Petra.Obexer@i-med.ac.at
Keywords: tubulin-inhibition, autophagy, NOXA, BCLXL, BIRC5/Survivin
Received: June 21, 2016 Accepted: March 08, 2017 Published: March 22, 2017
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.
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