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

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, an...

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Published in:The Journal of nutritional biochemistry 2016-05, Vol.31, p.28-37
Main Authors: Tan, Jen-Kit, Then, Sue-Mian, Mazlan, Musalmah, Raja Abdul Rahman, Raja Noor Zaliha, Jamal, Rahman, Wan Ngah, Wan Zurinah
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Bcl-2
BH3 mimetic
Cell Line, Tumor
Chromans - pharmacology
Gamma-tocotrienol
Humans
Molecular Mimicry
Neuroblastoma
Neuroblastoma - pathology
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Proto-Oncogene Proteins - chemistry
Proto-Oncogene Proteins - pharmacology
Vitamin E
Vitamin E - analogs & derivatives
Vitamin E - pharmacology
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Summary: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.
ISSN:0955-2863
1873-4847
DOI:10.1016/j.jnutbio.2015.12.019