|M.Sc Student||Shandalov Yulia|
|Subject||Modulation of Apoptosis by the Translocator Protein (TSPO)|
in Relation to Brain Cancer
|Department||Department of Medicine||Supervisor||Professor Emeritus Moshe Gavish|
|Full Thesis text|
Previous studies have shown that the Translocator protein (TSPO) appears to be involved in different cellular functions, among these functions it has been shown that TSPO is involved in apoptosis. Furthermore, it has been shown that TSPO is mainly located in the outer mitochondrial membrane (OMM) where it is found in interaction with other proteins. Among these proteins are the voltage dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT), which are components of the mitochondrial permeability transition pore (MPTP).
In the present study, we focused on the role of TSPO in apoptosis. We tried to determine how TSPO may modulate apoptosis. We suggest that because of it's interaction with the MPTP, the TSPO may modulate apoptosis via the mitochondrial apoptosis pathway. To investigate this we used the antineoplastic drug, Erucylphosphohomocholine (ErPC3), which is known to cause apoptosis via the mitochondrial apoptosis pathway. We used the human glioblastoma cell lines, U118MG, A172, and U87MG, to investigate the potential role of TSPO in the activation of the mitochondrial apoptosis pathway.
We found that ErPC3 cause cell death, which can be reduced by the TSPO specific ligand, PK 11195. Within the present study, we found that ErPC3 causes a collapse of the ΔΨm, which is known to be an initial step of the mitochondrial apoptosis pathway. We also found that ErPC3 causes cardiolipins peroxidation. This is indicative of reactive oxygen species' (ROS) generation at the mitochondrial level. We found that application of PK 11195 is protective against all ErPC3 effects mentioned above (i.e. cell death, apoptosis, collapse of the ΔΨm, and ROS generation).
As a result of this study, we suggest a possible mechanism to TSPO regulation of the mitochondrial apoptosis pathway. Furthermore we suggest that TSPO plays a pivotal role in the mediation of apoptosis in glioblastoma cell lines. With the present study we found that TSPO has two very important roles in the mediation of mitochondrial apoptosis: the first one is by inducing collapse of ΔΨm and the second one is by inducing ROS generation in the mitochondrial level followed by cardiolipins oxidation. The data of the present study, in addition to data from other studies, indicate that ROS generation under the control of TSPO may participate in the activation of the two step process of cytochrome c dissociation from cardiolipins. Subsequently, the mitochondrial release of cytochrome c activates the mitochondrial apoptosis pathway.