Up-regulation of c-Jun-NH2-kinase pathway contributes to the induction of mitochondria-mediated apoptosis by alpha-tocopheryl succinate in human prostate cancer cells.
Previously, alpha-tocopheryl succinate (alpha-TOS) has been reported to induce caspase-mediated apoptosis in PC-3 human prostate cancer cells. Caspase-9 was among several initiator caspases activated by alpha-TOS, suggesting a potential contribution of the intrinsic apoptotic pathway in mediating the response to alpha-TOS. Gene expression microarray was carried out as a screen to identify novel signaling molecules modulated by alpha-TOS, with a special focus on those known to play a role in mitochondria-mediated apoptosis. We discovered that Ask1, GADD45beta, and Sek1, three key components of the stress-activated mitogen-activated protein kinase pathway, are novel targets of alpha-TOS. Western blot analysis showed increased levels of phospho-Sek1 and phospho-c-Jun-NH2-kinase (JNK) in addition to total Ask1, GADD45beta, and Sek1. alpha-TOS also altered JNK-specific phosphorylation of Bcl-2 and Bim in a manner consistent with enhanced mitochondrial translocation of Bax and Bim. Because the expression level of most Bcl-2 family members remained unchanged, the posttranslational modification of Bcl-2 and Bim by JNK is likely to be a driving force in alpha-TOS activation of the intrinsic apoptotic pathway. Based on our findings, we propose a working model to capture the salient features of the apoptotic signaling circuitry of alpha-TOS.
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Ke
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Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Hawthorn
Lesleyann
L
Ip
Clement
C
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D016588:Anticarcinogenic Agents; C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D014810:Vitamin E; D048031:JNK Mitogen-Activated Protein Kinases; D024505:Tocopherols