Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs
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 apopto...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12935-019-0876-0 |
| _version_ | 1818505508677484544 |
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| author | Rony A. Francois Anying Zhang Kazim Husain Chen Wang Sean Hutchinson Michael Kongnyuy Surinder K. Batra Domenico Coppola Said M. Sebti Mokenge P. Malafa |
| author_facet | Rony A. Francois Anying Zhang Kazim Husain Chen Wang Sean Hutchinson Michael Kongnyuy Surinder K. Batra Domenico Coppola Said M. Sebti Mokenge P. Malafa |
| author_sort | Rony A. Francois |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T21:51:44Z |
| format | Article |
| id | doaj.art-4b1eb33314e540faa53a9f54910cd308 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-10T21:51:44Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-4b1eb33314e540faa53a9f54910cd3082022-12-22T01:32:11ZengBMCCancer Cell International1475-28672019-07-0119111510.1186/s12935-019-0876-0Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPsRony A. Francois0Anying Zhang1Kazim Husain2Chen Wang3Sean Hutchinson4Michael Kongnyuy5Surinder K. Batra6Domenico Coppola7Said M. Sebti8Mokenge P. Malafa9Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteGastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteGastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteGastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteGastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteGastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical CenterDepartment of Anatomical Pathology, H. Lee Moffitt Cancer Center and Research InstituteDrug Discovery Program, H. Lee Moffitt Cancer Center and Research InstituteGastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research InstituteAbstract 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.http://link.springer.com/article/10.1186/s12935-019-0876-0δ-TocotrienolPancreatic cancerApoptosisTRAILc-FLIP |
| spellingShingle | Rony A. Francois Anying Zhang Kazim Husain Chen Wang Sean Hutchinson Michael Kongnyuy Surinder K. Batra Domenico Coppola Said M. Sebti Mokenge P. Malafa Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs Cancer Cell International δ-Tocotrienol Pancreatic cancer Apoptosis TRAIL c-FLIP |
| title | Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs |
| title_full | Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs |
| title_fullStr | Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs |
| title_full_unstemmed | Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs |
| title_short | Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs |
| title_sort | vitamin e δ tocotrienol sensitizes human pancreatic cancer cells to trail induced apoptosis through proteasome mediated down regulation of c flips |
| topic | δ-Tocotrienol Pancreatic cancer Apoptosis TRAIL c-FLIP |
| url | http://link.springer.com/article/10.1186/s12935-019-0876-0 |
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