Abstract
BackgroundVitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects.MethodsWe report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.ResultsWhen combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, 2, 3 or death receptors 4 and 5. Enforced expression of c-FLIP substantially attenuated VEDT/TRAIL-induced apoptosis. Thus, c-FLIP reduction plays an important part in mediating VEDT/TRAIL-induced apoptosis. Moreover, VEDT increased c-FLIP ubiquitination and degradation but did not affect its transcription, suggesting that VEDT decreases c-FLIP levels through promoting its degradation. Of note, degradation of c-FLIP and enhanced TRAIL-induced apoptosis in pancreatic cancer cells were observed only with the anticancer bioactive vitamin E compounds δ-, γ-, and β-tocotrienol but not with the anticancer inactive vitamin E compounds α-tocotrienol and α-, β-, γ-, and δ-tocopherol.Conclusionsc-FLIP degradation is a key event for death receptor-induced apoptosis by anticancer bioactive vitamin E compounds in pancreatic cancer cells. Moreover, VEDT augmented TRAIL inhibition of pancreatic tumor growth and induction of apoptosis in vivo. Combination therapy with TRAIL agonists and bioactive vitamin E compounds may offer a novel strategy for pancreatic cancer intervention.
Highlights
Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects
Vitamin E delta-tocotrienol (VEDT) inhibits the growth of human pancreatic cancer cells in vitro and in vivo and induces apoptosis We first examined whether VEDT alone could inhibit the survival of a panel of human pancreatic cancer cells
Because decreased cell survival may be caused by many processes, we investigated whether VEDT survival inhibition could be attributed to increased apoptosis
Summary
Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects. Apoptosis is controlled by 2 major signaling pathways: the extrinsic pathway, initiated by death receptors, and the intrinsic pathway, initiated via the mitochondria [7, 8] Crosstalk between these 2 pathways is mediated by signaling involving the proapoptotic protein Bid [9]. Activation of the extrinsic death receptor-mediated apoptotic pathway has received attention as a potential strategy for cancer treatment because its activation preferentially induces apoptosis in transformed or malignant cells but not in most normal cells. Recent studies have shown that many types of cancer cells, including pancreatic ductal adenocarcinoma cells, are resistant to the apoptotic effects of TRAIL [11,12,13], suggesting that treatment with TRAIL alone may not be sufficient for treating pancreatic cancer. Sensitizers capable of overcoming TRAIL resistance in pancreatic cancer cells are needed to establish more effective TRAIL-based pancreatic cancer therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
