Carcinogenesis Advance Access originally published online on August 14, 2007
Carcinogenesis 2007 28(9):1937-1945; doi:10.1093/carcin/bgm143
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Critical role of oxidative stress and sustained JNK activation in aloe-emodin-mediated apoptotic cell death in human hepatoma cells
1 Department of Biochemistry
2 Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine
3 Department of Biological Sciences, Faculty of Science
4 Office of Life Sciences, National University of Singapore, Singapore, 117597
* To whom correspondence should be addressed. Tel: +65 6516 4982; Fax: +65 6779 1489; Email: cofongcn{at}nus.edu.sg
Aloe-emodin (AE), one of the main bioactive anthraquinones of Rheum palmatum, possesses potent antitumor properties. Our previous proteomic study revealed that AE-induced apoptosis was associated with oxidative stress and oxidation of many redox-sensitive proteins. In this study, we aimed to further dissect the cell death-signaling pathways in AE-induced apoptosis. AE was found to cause redox imbalance and deplete the intracellular-reduced glutathione (GSH). Manipulation of the intracellular GSH with buthionine-L-sulfoximine (a GSH synthesis inhibitor) sensitized, and with glutathione monomethyl ester (a GSH donor) protected the AE-induced apoptosis, respectively. More importantly, AE treatment led to evident and sustained activation of c-Jun N-terminal kinase (JNK), an important stress-responsive mitogen-activated protein kinase (MAPK). Over-expression of antioxidant gene sod1 significantly reduced AE-induced JNK activation and cell death, suggesting that oxidative stress-mediated JNK is the effector molecule in AE-induced apoptosis. Such a notion was clearly supported by subsequent studies in which JNK activation was inhibited by JNK inhibitor, JNK small interfering RNA knockdown or over-expression of dominant-negative JNK. In addition, we provided evidence demonstrating the critical role of apoptosis signal-regulating kinase 1, a well-established MAPK kinase kinase, in AE-induced JNK activation and apoptotic cell death. Finally, we showed that dissociation of inactive JNK–Glutathione S-transferase pi (GST-pi) complex was also involved in JNK activation through GST-pi oxidation. Taken together, these results suggest that AE-induced apoptotic cell death is mediated via oxidative stress and sustained JNK activation.
Abbreviations: AE, aloe-emodin; ASK1, apoptosis signal-regulating kinase 1; ERK, extracellular signal-regulated kinase; GSH, reduced glutathione; GSSG, oxidized glutathione; GST-pi, Glutathione S-transferase pi; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PRDX, peroxiredoxin; PARP, poly(ADP-ribose) polymerase; ROS, reactive oxygen species; SDS, sodium dodecyl sulfate; siRNA, small interfering RNA; SOD, superoxide dismutase
Received March 9, 2007; revised May 14, 2007; accepted June 11, 2007.
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