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The hallmark of cancer cells is deregulated growth, inhibition of differentiation, and delay or blockage of programmed cell death. Tumor cells that are independent of extraand/or intracellular regulatory mechanisms due to mutations in proto-oncogenes and tumor suppressors acquire the ability of uncontrolled proliferation and invasion into other tissues. FOXO (FOXO1, FOXO3, FOXO4, FOXO6) transcription factors control apoptosis, stress resistance and longevity in mammalian cells. Their activity and subcellular localization is regulated by phosphorylation on conserved serine/threonin residues via protein kinase B (PKB) and stress-induced kinases. Hyperactivation of PKB contributes to the inactivation of FOXO3 and predicts poor outcome for neuroblastoma patients. Depending on their posttranslational modifications and cellular context FOXO transcription factors exert diverse functions thereby either inducing cell death but also cell survival and resistance to environmental stress. Although FOXO transcription factors share the same DNA binding motive and seem to have overlapping functions, knock out animals for single FOXO family members show different defects: Whereas FOXO1 knock-out mice die during embryonic development due to defective vasculature, FOXO3 and FOXO4 knock out mice show a mild phenotype. However, conditional triple-knock-out mice provide evidence that FOXO1, FOXO3 and FOXO4 are critically involved in the maintenance of the hematopoietic stem cell population and the regulation of endothelial cell homeostasis. Consistent with their putative role as tumor suppressors, in cultured neuroblastoma cells the activation of FOXO3 triggers the intrinsic death pathway and induces programmed cell death via induction of the proapoptotic BH3-only proteins BCL2L11/Bim and PMAIP1/Noxa. Surprisingly, in neuroblastoma cells FOXO3-mediated cell death depends on the accumulation of reactive oxygen species (ROS). Activation of FOXO3 also causes the repression of the apoptosisinhibitor protein Survivin and determines sensitivity of neuroblastoma cells to DNAdamaging chemotherapeutic agents. More recently it was shown that beside its function as a tumor suppressor FOXO3 might also facilitate cancer cell survival under certain circumstances. In other tumor types FOXO3 also induces detoxification and stress resistance

FOXO Transcription Factors as Potential Therapeutic Targets in Neuroblastoma