Fenretinide-induced ER-Stress and Apoptosis in Neuroectodermal Tumors

The synthetic retinoid fenretinide induces apoptosis via oxidative stress, and this is accompanied by induction of the ER stress transcription factor GADD153; however, the link between the induction of oxidative stress and Gadd153 is not yet clear. Here we show that fenretinide-induced cellular oxidative status results in ER-stress and subsequent apoptosis. ER-stress induction is mediated by eIF2a phosphorilation and Xbp-I splicing. Furthermore, results from microarray analysis revealed the involvement of other two ER-related genes, ERdj5 and ERp57, as genes upregulated during fenretinide-induced ER-stress in neuroectodermal tumor cells. siRNA of either ERdj5 and ERp57 resulted in enhanced sensitivity of neuroectodermal cells to apoptosis in response to fenretinide. These results demonstrate as ER-stress plays a pivotal role in fenretinide-induced cell death of neuroectodermal tumor cells and suggest as ERdj5 and ERp57 may represent new targets for future drug development