C10ORF10/DEPP, a transcriptional target of FOXO3, regulates ROS-sensitivity in human neuroblastoma.

BACKGROUND:FOXO transcription factors control cellular levels of reactive oxygen species which critically contribute to cell survival and cell death in neuroblastoma. In the present study we investigated the regulation of C10orf10/DEPP by the transcription factor FOXO3. As a physiological function of C10orf10/DEPP has not been described so far we analyzed its effects on cellular detoxification and death sensitization in human neuroblastoma cells. METHODS:The effect of DEPP on cellular duanyu1670 was measured by catalase activity assay and live cell fluorescence microscopy using the dye reduced MitoTracker Red The cellular localization of DEPP was determined by confocal microscopy of EYFP-tagged DEPP, fluorescent peroxisomal- and mitochondrial probes and co-immunoprecipitation of the PEX7 receptor. RESULTS:We report for the first time that DEPP regulates duanyu1670 detoxification and localizes to peroxisomes and mitochondria in neuroblastoma cells. FOXO3-mediated apoptosis involves a biphasic duanyu1670 accumulation. Knockdown of DEPP prevented the primary and secondary duanyu1670 wave during FOXO3 activation and attenuated FOXO3- and H2O2-induced apoptosis. Conditional overexpression of DEPP elevates cellular duanyu1670 levels and sensitizes to H2O2 and etoposide-induced cell death. In neuronal cells, cellular duanyu1670 are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that allows binding to the PEX7 receptor and import into peroxisomes, we analyzed the effect of DEPP on cellular detoxification by measuring enzyme activity of catalase. Catalase activity was reduced in DEPP-overexpressing cells and significantly increased in DEPP-knockdown cells. DEPP directly interacts with the PEX7 receptor and localizes to the peroxisomal compartment. In parallel, the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARG), a critical regulator of catalase enzyme activity, was strongly upregulated in DEPP-knockdown cells. CONCLUSION:The combined data indicate that in neuroblastoma DEPP localizes to peroxisomes and mitochondria and impairs cellular duanyu1670 detoxification, which sensitizes tumor cells to cell death.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}