Therapy-resistant acute lymphoblastic leukemia (ALL) cells inactivate FOXO3 to escape apoptosis induction by TRAIL and Noxa
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Michael J. Ausserlechner1,3,*, Christina Salvador1,*, Andrea Deutschmann1,3, Martin Bodner1,3,5, Giampietro Viola4, Roberta Bortolozzi4, Giuseppe Basso4, Judith Hagenbuchner2,3 and Petra Obexer2,3
1 Department of Pediatrics I, Medical University Innsbruck, Austria
2 Department of Pediatrics II, Medical University Innsbruck, Austria
3 Tyrolean Cancer Research Institute, Innsbruck, Austria
4 Department of Woman’s and Child’s Health, Oncohematology laboratory University of Padova, Padova-Italy
5 present affiliation: Institute of Legal Medicine, Innsbruck Medical University, Innsbruck, Austria
* These authors contributed equally to this work
Judith Hagenbuchner, email:
Keywords: FOXO3/FKHRL1, T-ALL, p16/INK4A, BH3-only proteins, TRAIL
Received: March 27, 2013 Accepted: June 23, 2013 Published: June 25, 2013
Forkhead transcription factors (FOXO) are downstream targets of the phosphoinositol-3-kinase (PI3K) protein kinase B (PKB) signaling cascade and play a pivotal role in cell differentiation, cell cycle and apoptosis. We found that cells from prednisone-resistant T-acute lymphoblastic leukemia (T-ALL) patients showed cytoplasmic localization of FOXO3 in comparison to prednisone-sensitive patients suggesting its inactivation. To determine the impact of FOXO3, T-ALL cells were infected with a 4OH-tamoxifen-regulated, phosphorylation-independent FOXO3(A3)ERtm allele. After FOXO3-activation these cells undergo caspase-dependent apoptosis. FOXO3 induces the death ligand TRAIL and the BH3-only protein Noxa implicating extrinsic as well as intrinsic death signaling. Whereas dnFADD partially inhibited cell death, CrmA and dnBID efficiently rescued ALL cells after FOXO3 activation, suggesting a caspase-8 amplifying feedback loop downstream of FADD. Knockdown of TRAIL and Noxa reduced FOXO3-induced apoptosis, implicating that mitochondrial destabilization amplifies TRAIL-signaling. The-reconstitution of the cell cycle inhibitor p16INK4A, which sensitizes ALL cells to mitochondria-induced cell death, represses FOXO3 protein levels and reduces the dependency of these leukemia cells on PI3K-PKB signaling. This suggests that if p16INK4A is deleted during leukemia development, FOXO3 levels elevate and FOXO3 has to be inactivated by deregulation of the PI3K-PKB pathway to prevent FOXO3-induced cell death.
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