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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.

Author information

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

Abstract

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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.

KEYWORDS:

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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