Abstract
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.
Highlights
Forkhead transcription factors (FOXO) are downstream targets of the phosphoinositol-3-kinase (PI3K) protein kinase B-(PKB)-signaling pathway [1]
In the present study we demonstrate that activation of the transcription factor FOXO3 induces apoptotic cell death in therapy-resistant T-acute lymphoblastic leukemia (T-ALL) cells
We found cytoplasmic localization of FOXO3 predominantly in the bone-marrow cells from patients who poorly respond to prednisone treatment (Fig 1)
Summary
Forkhead transcription factors (FOXO) are downstream targets of the phosphoinositol-3-kinase (PI3K) protein kinase B-(PKB)-signaling pathway [1]. Due to deregulation of the PI3K-PKB pathway, these transcription factors are inactivated in the majority of human malignancies, either through hyperactivation of PKB itself or due to the loss of inhibitors of the PI3K-signaling, such as PTEN [3]. One explanation for PKB hyperactivation might be that T-ALL cells frequently carry a heterozygous deletion of the PTEN gene locus [6], which leads to increased PI3K-PKB signaling and thereby inactivation of the PKB target FOXO3 in leukemia cells. Inhibitors of the PI3K-PKB pathway, which induce apoptosis in different leukemia cells are already in the focus of several preclinical studies but the critical target in this network has not been discovered yet [4, 10]
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