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J Nutr Biochem. 2016 May;31:28-37. doi: 10.1016/j.jnutbio.2015.12.019. Epub 2016 Feb 9.

Gamma-tocotrienol acts as a BH3 mimetic to induce apoptosis in neuroblastoma SH-SY5Y cells.

Author information

1
UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia. Electronic address: tanjenkit@gmail.com.
2
Department of Biomedical Sciences, Faculty of Sciences, The University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia. Electronic address: then.sue-mian@nottingham.edu.my.
3
Faculty of Medicine, Universiti Teknologi MARA, 47000, Sungai Buluh, Selangor, Malaysia. Electronic address: musalmah6393@salam.uitm.edu.my.
4
Enzyme and Microbial Technology Research Center, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia; Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia. Electronic address: rnzaliha@upm.edu.my.
5
UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia. Electronic address: rahmanj@ppukm.ukm.edu.my.
6
UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia; Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia. Electronic address: wanzurinah@ppukm.ukm.edu.my.

Abstract

Bcl-2 family proteins are crucial regulators of apoptosis. Both pro- and antiapoptotic members exist, and overexpression of the latter facilitates evasion of apoptosis in many cancer types. Bcl-2 homology domain 3 (BH3) mimetics are small molecule inhibitors of antiapoptotic Bcl-2 family members, and these inhibitors are promising anticancer agents. In this study, we report that gamma-tocotrienol (γT3), an isomer of vitamin E, can inhibit Bcl-2 to induce apoptosis. We demonstrate that γT3 induces cell death in human neuroblastoma SH-SY5Y cells by depolarising the mitochondrial membrane potential, enabling release of cytochrome c to the cytosol and increasing the activities of caspases-9 and -3. Treatment of cells with inhibitors of Bax or caspase-9 attenuated the cell death induced by γT3. Simulated docking analysis suggested that γT3 binds at the hydrophobic groove of Bcl-2, while a binding assay showed that γT3 competed with a fluorescent probe to bind at the hydrophobic groove. Our data suggest that γT3 mimics the action of BH3-only protein by binding to the hydrophobic groove of Bcl-2 and inducing apoptosis via the intrinsic pathway in a Bax- and caspase-9-dependent manner.

KEYWORDS:

Apoptosis; BH3 mimetic; Bcl-2; Gamma-tocotrienol; Neuroblastoma; Vitamin E

PMID:
27133421
DOI:
10.1016/j.jnutbio.2015.12.019
[Indexed for MEDLINE]

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