Therapy-resistant acute lymphoblastic leukemia (ALL) cells inactivate FOXO3 to escape apoptosis induction by TRAIL and Noxa

被引:21
作者
Ausserlechner, Michael J. [1 ,3 ]
Salvador, Christina [1 ]
Deutschmann, Andrea [1 ,3 ]
Bodner, Martin [1 ,3 ]
Viola, Giampietro [4 ]
Bortolozzi, Roberta [4 ]
Basso, Giuseppe [4 ]
Hagenbuchner, Judith [2 ,3 ]
Obexer, Petra [2 ,3 ]
机构
[1] Med Univ Innsbruck, Dept Pediat 1, A-6020 Innsbruck, Austria
[2] Med Univ Innsbruck, Dept Pediat 2, A-6020 Innsbruck, Austria
[3] Tyrolean Canc Res Inst, Innsbruck, Austria
[4] Univ Padua, Oncohematol Lab, Dept Womans & Childs Hlth, Padua, Italy
关键词
FOXO3/FKHRL1; T-ALL; p16/INK4A; BH3-only proteins; TRAIL; HEMATOPOIETIC STEM-CELLS; KAPPA-B; EXPRESSION; PATHWAY; GENE; BIM; NEUROBLASTOMA; SURVIVAL; DELETION; KINASE;
D O I
10.18632/oncotarget.953
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 p16(INK4A), 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 p16(INK4A) 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.
引用
收藏
页码:995 / 1007
页数:13
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