PLoS ONE (Oct 2009)

Converting redox signaling to apoptotic activities by stress-responsive regulators HSF1 and NRF2 in fenretinide treated cancer cells.

  • Kankan Wang,
  • Hai Fang,
  • Dakai Xiao,
  • Xuehua Zhu,
  • Miaomiao He,
  • Xiaoling Pan,
  • Jiantao Shi,
  • Hui Zhang,
  • Xiaohong Jia,
  • Yanzhi Du,
  • Ji Zhang

DOI
https://doi.org/10.1371/journal.pone.0007538
Journal volume & issue
Vol. 4, no. 10
p. e7538

Abstract

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BackgroundPharmacological 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.Methodology/principal findingsWe 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.Conclusions/significanceThis 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.