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Originally published as MBC in Press, 10.1091/mbc.E08-07-0699 on February 18, 2009 Originally published as MBC in Press, 10.1091/mbc.E08-07-0699 on February 11, 2009

Vol. 20, Issue 7, 2041-2048, April 1, 2009

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Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA Damage-induced Apoptosis

Petra Obexer*,{dagger}, Judith Hagenbuchner*, Thomas Unterkircher{ddagger}, Nora Sachsenmaier*, Christoph Seifarth*, Günther Böck§, Verena Porto*, Kathrin Geiger*, and Michael Ausserlechner*,{ddagger}

*Tyrolean Cancer Research Institute, A-6020 Innsbruck, Austria; and Departments of {dagger}Pediatrics IV, {ddagger}Pediatrics II, and §Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University, A-6020 Innsbruck, Austria

Submitted July 9, 2008; Revised January 28, 2008; Accepted January 30, 2009
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-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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-07-0699) on February 18, 2009.

Address correspondence to: Petra Obexer (petra.obexer{at}i-med.ac.at)

Abbreviations used: 4OHT, 4-hydroxy-tamoxifen; FKHRL1, forkhead transcription factor-like 1; NB, neuroblastoma; Surv, Survivin.






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