Alpha-tocopherol-mediated caspase-3 up-regulation enhances susceptibility to apoptotic stimuli.
Although alpha-tocopherol is known as an essential micronutrient involved in various oxidative stress-related processes, its non-antioxidant activities have only been characterized in recent years. In this study, we reveal that (+)-alpha-tocopherol [RRR-alpha-tocopherol] enhances cellular susceptibility to both oxidative and non-oxidative apoptosis-inducing stimuli through up-regulation of caspase-3/CPP32 expression in several human cell lines. Exposure of (+)-alpha-tocopherol pretreated cells to known apoptosis-inducing stimuli, such as Fas, H(2)O(2), or etoposide, resulted in an increase in cellular apoptotsis. In addition, (+)-alpha-tocopherol also elevated the pro-caspase-3 protein level and mRNA expression in a time- and dose-dependent manner, while other tocopherol analogues showed no effect. Experiments using a GC-specific DNA binding agent, mithramycin A, and an electrophoretic mobility shift assay demonstrated that Sp1 might mediate the enhanced expression of caspase-3. Our results also confirmed that (+)-alpha-tocopherol promotes the expression, but not the activation, of caspase-3 in various human cell lines. These findings provide biological evidence showing that (+)-alpha-tocopherol can amplify the apoptotic response by up-regulating the expression of pro-caspase-3.
Miyoshi
Noriyuki
N
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Naniwa
Kisa
K
Kumagai
Takeshi
T
Uchida
Koji
K
Osawa
Toshihiko
T
Nakamura
Yoshimasa
Y
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007136:Immunoglobulins / Q000378:metabolism*; D019169:Jurkat Cells; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D024502:alpha-Tocopherol / Q000378:metabolism* / Q000494:pharmacology; D019014:fas Receptor
C491901:FAS protein, human; D007136:Immunoglobulins; D018124:Receptors, Tumor Necrosis Factor; C090698:SP1 antigen; D019014:fas Receptor; D005047:Etoposide; D006861:Hydrogen Peroxide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D024502:alpha-Tocopherol