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.
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Kankan
K
Wang
Hai
H
Fang
Dakai
D
Xiao
Xuehua
X
Zhu
Miaomiao
M
He
Xiaoling
X
Pan
Jiantao
J
Shi
Hui
H
Zhang
Xiaohong
X
Jia
Yanzhi
Y
Du
Ji
J
Zhang
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