Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 20, Issue 7, Pages 2041-2048Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-07-0699
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Funding
- Children Cancer Society of Tyrol and Vorarlberg
- Children's Cancer Research Institute (CCRI)
- Sudtiroler Krebshilfe
- OeNB Anniversary Fund [11436, 12582]
- Tyrolean Science Fund (TWF)
- Osterreichische Krebshilfe-Oberosterreich
- Tiroler Landesk-rankenanstalten Ges.m.b.H. (TILAK)
- Tyrolean Cancer Society
- Department of Health-Care, Autonomy of South Tyrol
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The phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) pathway regulates survival and chemotherapy resistance of neuronal cells, and its deregulation in neuroblastoma (NB) tumors predicts an adverse clinical outcome. Here, we show that inhibition of PI3K-PKB signaling in human NB cells induces nuclear translocation of FOXO3/FKHRL1, represses the prosurvival protein BIRC5/Survivin, and sensitizes to DNA-damaging agents. To specifically address whether FKHRL1 contributes to Survivin regulation, we introduced a 4-hydroxy-tamoxifen-regulated FKHRL1(A3) ERtm allele into NB cells. Conditional FKHRL1 activation repressed Survivin transcription and protein expression. Transgenic Survivin exerted a significant antiapoptotic effect and prevented the accumulation of Bim and Bax at mitochondria, the loss of mitochondrial membrane potential as well as the release of cytochrome c during FKHRL1-induced apoptosis. In concordance, Survivin knockdown by retroviral short hairpin RNA technology accelerated FKHRL1-induced apoptosis. Low-dose activation of FKHRL1 sensitized to the DNA-damaging agents doxorubicin and etoposide, whereas the overexpression of Survivin diminished FKHRL1 sensitization to these drugs. These results suggest that repression of Survivin by FKHRL1 facilitates FKHRL1-induced apoptosis and sensitizes to cell death induced by DNA-damaging agents, which supports the central role of PI3K-PKB-FKHRL1 signaling in drug resistance of human NB.
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