Coordination of Fenretinide-Induced Apoptosis by Stress-Responsive Regulators in Leukemia Cells

• Published in: Blood Vol. 112; no. 11; p. 4730
• Main Authors: Wang, Kankan, Fang, Hai, Xiao, Da-Kai, Zhu, Xue-Hua, He, Miao- Miao, Pan, Xiao-Ling, Chen, Sai-Juan, Zhang, Ji
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.11.2008
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V112.11.4730.4730

Pharmacological intervention affecting intracellular redox balance often results in oxidative stress-mediated apoptosis, which also represents a new direction for cancer therapeutic designs. However, mechanistic links between redox signals and their downstream effects on apoptosis have not yet been elucidated in cancer cells. Here, we report a detailed analysis of fenretinide-induced apoptosis in leukemia-derived cells through a systems approach, integrating experimental and computational methods together with advanced data mining tools. Robust transcriptome profiling reveals numerous stress-responsive events at the temporal and spatial levels, including oxidative stress, endoplasmic reticulum stress/unfolded protein response, translational repression, proteasome activation, and apoptosis induction. Moreover, stress-responsive transcription factors, as highlighted by NRF2 and HSF1, play prominent roles in the configuration of these relevant events. Several lines of evidence suggest that these stress-responsive regulators and thus their target genes are involved not only in converting oxidative signaling into downstream effects but also in coordinating the progression of cell apoptosis. 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.