ABSTRACT: Pharmacological intervention of redox balance in cancer cells often results in oxidative stress-mediated apoptosis, attracting much attention for the development of a new generation of targeted therapy in cancer. However, little is known about mechanisms underlying the conversion from oxidative signaling to downstream activities leading cells to death. We here report a systematic detection of transcriptome changes in response to oxidative signals generated in leukemia cells upon fenretinide treatment, implicating the occurrence of numerous stress-responsive events during the fenretinide induced apoptosis, such as redox response, endoplasmic reticulum stress/unfolded protein response, translational repression and proteasome activation. Moreover, the configuration of these relevant events is primarily orchestrated by stress responsive transcription factors, as typically highlighted by NF-E2-related factor-2 (NRF2) and heat shock factor 1 (HSF1). Several lines of evidence suggest that the coordinated regulation of these transcription factors and thus their downstream genes are involved in converting oxidative signaling into downstream stress-responsive events regulating pro-apoptotic and apoptotic activities at the temporal and spatial levels, typifying oxidative stress-mediated programmed death rather than survival in cancer cells. This study provides a roadmap for understanding oxidative stress-mediated apoptosis in cancer cells, which may be further developed into more sophisticated therapeutic protocols, as implicated by synergistic induction of cell apoptosis using proteasome inhibitors with fenretinide. Time-series experiment, fenretinide treated NB4 cells at 19 time points (i.e., 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54 and 60 hours) and untreated NB4 cells at 4 time points (i.e., 0, 8, 12 and 15 hours).
