Faculty of Science Research Talk : How Gamma-Tocotrienol,A Vitamin E Isomer Mimics BH3-Only Proteins to Kill Euroblastoma Cells

Name: Dr Then Sue Mian – School of Biomedical Science

Title: How Gamma-Tocotrienol,A Vitamin E Isomer Mimics BH3-Only Proteins to Kill Euroblastoma Cells

Abstract:

The dysregulation of apoptosis process is the hallmark of cancer, with B-cell lymphoma 2 (Bcl-2) family proteins playing a crucial role in the initiation of the intrinsic apoptosis pathway. BH3-only proteins trigger apoptosis by binding to prosurvival proteins such as Bcl-2 to release the proapoptotic proteins such as Bax, Bak from sequestration of Bcl-2 protein. Therefore, small molecules (BH3 mimetics) mimicking BH3-only proteins could be potential anticancer agents. In this study, we examined the potential action of gamma-tocotrienol,γT3 (a vitamin E isomer) as an antagonist of Bcl-2 protein in human neuroblastoma SH-SY5Y cells. Previous studies have showed that γT3 was able to induce cancer cell death via several cellular pathways. However, our data present the first report of γT3 with BH3 mimetic-like properties as the possible mechanism of action. Our results showed that γT3 reduced cell viability of neuroblastoma in a concentration dependent manner. γT3 induced apoptosis by depolarizing mitochondrial membrane potential and releasing cytochrome c from mitochondria to cytosol. γT3 also induced caspase-9 and caspase-3 activities while caspase-8 activity was not affected. These result indicated that γT3 induced apoptosis by intrinsic pathway. In silico docking analysis suggested γT3 binds to BH3 domain of Bcl-2 protein. In vitro binding assay demonstrated γT3 was bound to Bcl-2 protein. In conclusion, our data suggested γT3 induced apoptosis by inhibiting Bcl-2 protein function by binding to the BH3 domain to initiate the apoptosis process.