Abstract 1862: Capsaicin mediated activation of JNK/FOXO/BIM causes apoptosis in pancreatic cancer cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Capsaicin, a homovanillic acid derivative (N-vanillyl-8-methyl-nonenamide) is an active component of chili pepper. We previously reported that capsaicin mediated generation of reactive oxygen species (ROS) causes apoptosis in pancreatic cancer cells. In the present study, we investigated the potential mechanism of capsaicin mediated apoptosis in pancreatic cancer cells. In a time and concentration dependent study, capsaicin treatment activated c-Jun N terminal kinase (JNK) in BxPC-3, AsPC-1 and L3.6PL pancreatic cancer cells. Further, capsaicin induced activation of JNK in turn activated FOXO1 by phosphorylating at Ser 256 and pro-apoptotic protein BIM at Ser 69. The expression of BIM also increased in response to capsaicin treatment. Capsaicin treatment also caused cleavage of caspase-9, caspase-3 and PARP resulting in apoptosis. Blocking capsaicin mediated activation of JNK by JNK-specific inhibitor SP600125 attenuated nuclear localization of FOXO-1, activation of BIM and abrogated capsaicin-induced apoptosis. To confirm the involvement of ROS in the activation of JNK, FOXO and Bim, cells were treated with antioxidants catalase and EUK (mimetic of catalase) prior to capsaicin treatment. Our results reveal that both the antioxidants blocked capsaicin mediated JNK/FOXO/BIM activation and protected the cells from apoptosis. Furthermore, silencing FOXO1 by siRNA blocked capsaicin-mediated activation of BIM and apoptosis. To further confirm the involvement of Bim in capsaicin-induced apoptosis, cells were transfected with BIM siRNA. Silencing Bim drastically reduced capsaicin-mediated cleavage of caspase-3 and PARP indicating the role of Bim in inducing apoptosis in our model. Taken together, our results suggest that ROS generated by capsaicin activates JNK and FOXO-1 which in turn activates BIM resulting in the cleavage of caspase-9/3 and PARP 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 1862. doi:10.1158/1538-7445.AM2011-1862