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


RESULTS
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.


CONCLUSIONS
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.
Wang
Kankan
K
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Fang
Hai
H
Xiao
Dakai
D
Zhu
Xuehua
X
He
Miaomiao
M
Pan
Xiaoling
X
Shi
Jiantao
J
Zhang
Hui
H
Jia
Xiaohong
X
Du
Yanzhi
Y
Zhang
Ji
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017313:Fenretinide / Q000737:chemistry* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D020298:U937 Cells
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D014157:Transcription Factors; D017313:Fenretinide; D010100:Oxygen