Abstract 190: Targeting ceramide and endoplasmic reticulum-stress in vitamin E induced apoptosis in human breast cancer cells

Abstract

Abstract Vitamin E consists of eight plant-derived forms classified as tocopherols (α, β, Δ, γ) and tocotrienols (α, β, Δ, γ) which have a chromanol ring and a saturated and unsaturated aliphatic side chain, respectively. The anti-cancer actions of tocopherols and tocotrienols are limited to the gamma and delta forms. Here, we report that both γ-tocopherol (γT) and γ-tocotrienol (γT3) display potent anti-cancer actions with γT3 being more potent. Both forms target similar pro-apoptotic and anti-apoptotic pathways. γT and γT3 induced apoptosis in human breast cancer cells by enhancing death-receptor DR5 mediated activation of caspase-8 and mitochondria dependent caspase-9, as well as by activating ER-stress markers: GADD153/ C/EBP homologous protein (CHOP), GRP-78, ATF-4 and eIF2α. JNK and CHOP are involved in DR5 mediated apoptosis triggered by both vitamin E forms. γT and γT3 decreased protein levels of anti-apoptotic factors c-FLIP, BCl-2 and survivin. Since ceramide is a known upstream inducer of ER-stress and downstream mediator of death receptor apoptotic pathway mediators, treatments with γT and γT3 were conducted in the presence of specific inhibitors of sphingomyelin hydrolysis, de novo ceramide pathways and ER-stress in order to distinguish between the pathways modulated by the vitamin E forms. Data show that both γT and γT3 induced apoptosis via activation of sphingomyelin hydrolysis and the de novo ceramide pathways; however, activation of the ER-stress pathway contributed to apoptosis induced by γT3 only. Taken together, our data suggest that γT3s more potent apoptotic effects in comparison to γT are due to the ability of γT3 to activate ER stress pathways. This better understanding of the anti-cancer properties and mechanistic actions by these two natural occurring agents in vitro provides the necessary impetus to test them in combination with other known anti-cancer agents in pre-clinical xenograft studies to identify novel and safer therapeutic strategies. Research funded by The Clayton Foundation for Research. 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 190. doi:10.1158/1538-7445.AM2011-190