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Cancer Cell Int. 2019 Jul 22;19:189. doi: 10.1186/s12935-019-0876-0. eCollection 2019.

Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs.

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1Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA.
2Department of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
3Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
4Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NB USA.
5Department of Anatomical Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA.
6Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA.
Contributed equally



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.


We 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.


When 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.


c-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.


Apoptosis; Pancreatic cancer; TRAIL; c-FLIP; δ-Tocotrienol

Conflict of interest statement

Competing interestsThe authors declare that they no competing interests.

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