Repression of BIRC5/survivin by FOXO3/FKHRL1 sensitizes human neuroblastoma cells to DNA damage-induced apoptosis

Mol Biol Cell. 2009 Apr;20(7):2041-8. doi: 10.1091/mbc.e08-07-0699. Epub 2009 Feb 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Apoptosis* / drug effects
  • Cell Line, Tumor
  • DNA Damage*
  • Doxorubicin / pharmacology
  • Drug Screening Assays, Antitumor
  • Etoposide / pharmacology
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins / antagonists & inhibitors*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neuroblastoma / enzymology
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Survivin
  • Transgenes


  • BIRC5 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • RNA, Small Interfering
  • Survivin
  • Etoposide
  • Doxorubicin
  • Proto-Oncogene Proteins c-akt