Abstract
Abstract Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) kinase kinase family plays an essential role in reactive oxygen species (ROS) induced cellular response. Thioredoxin (Trx), a redox sensitive protein binds to ASK1 and inhibits its activation. In our previous study, we have shown that capsaicin induced apoptosis in pancreatic cancer cells was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. In the present study, we evaluated the interaction of thioredoxin/ASK1 in pancreatic cancer cells. In a concentration dependent study, we observed that capsaicin treatment down regulated thioredoxin and increased the phosphorylation (activation) of ASK1 at Thr845 in AsPC-1 and BxPC-3 cells. ASK1 has been shown to activate JNK, which in turn activates MKK4/7 resulting in the cleavage of caspase-9, and caspase-3. In agreement, our results reveal that capsaicin treatment activated JNK, MKK4/7, caspase-9 and caspase-3. Interestingly, treatment of cells with antioxidants such as tiron or catalase blocked the activation of ASK1 cascade by capsaicin and protected the cells from apoptosis indicating the involvement of ROS in the activation of ASK1. To confirm the interaction of Trx/ASK1 and the dissociation of ASK1 by capsaicin in our model, BxPC-3 cell were transiently transfected with contructs encoding ASK1 fused to C-terminal hemaggutinin (HA) and flag tagged Trx. Our results reveal that Trx over expression suppressed the effects of capsaicin whereas ASK1 over expression enhanced the apoptosis-inducing effects of capsaicin. Taken together, our results suggest that ROS generated by capsaicin reduce Trx expression resulting in the activation of ASK1 and downstream effectors leading to apoptosis in pancreatic cancer cells. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3694. doi:10.1158/1538-7445.AM2011-3694
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