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

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• 作者：Jen-Kit Tan^a ; ^{tanjenkit@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Sue-Mian Then^b ; ^{then.sue-mian@nottingham.edu.my" class="auth_mail" title="E-mail the corresponding author} ; Musalmah Mazlan^c ; ^{musalmah6393@salam.uitm.edu.my" class="auth_mail" title="E-mail the corresponding author} ; Raja Noor Zaliha Raja Abdul Rahman^d ; ^e ; ^{rnzaliha@upm.edu.my" class="auth_mail" title="E-mail the corresponding author} ; Rahman Jamal^a ; ^{rahmanj@ppukm.ukm.edu.my" class="auth_mail" title="E-mail the corresponding author} ; Wan Zurinah Wan Ngah^a ; ^f ; ^{wanzurinah@ppukm.ukm.edu.my" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Gamma-tocotrienol ; BH3 mimetic ; Neuroblastoma ; Bcl-2 ; Apoptosis ; Vitamin E
• 刊名：Journal of Nutritional Biochemistry
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：31
• 期：Complete
• 页码：28-37
• 全文大小：826 K

文摘

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.