Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA-Damage-induced Apoptosis.
Mol Biol Cell. 2009 Feb 11;
Authors: Obexer P, Hagenbuchner J, Unterkircher T, Sachsenmaier N, Seifarth C, Böck G, Porto V, Geiger K, Ausserlechner M
Monitoring Editor: Kunxin Luo 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 (4OHT)-regulated FKHRL1(A3)ERtm allele into NB cells. Conditional FKHRL1 activation repressed Survivin transcription and protein expression. Transgenic Survivin exerted a significant anti-apoptotic 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 knock-down by retroviral shRNA 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.
PMID: 19211844 [PubMed - as supplied by publisher]