SIGNIFICANCE OF BAX/BCL-2 EXPRESSION RATIO DURING APOPTOTIC PATHWAYS OF HUMAN GLIOMA CELLS

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Elevation of intracellular ceramide levels has been observed in response to various extracellular stimuli including γ- irradiation, ultraviolet light, and the chemotherapeutic agents and causes apoptosis and/or cell cycle arrest. The addition of exogenous ceramide, such as cell-permeable C2-ceramide, has been associated with several anti proliferative responses including cell differentiation, apoptosis, and cell cycle arrest. Therefore, ceramide has been proposed as a mediator of apoptosis and as a coordinator of the cellular responses to stresses. To date, however, the interrelationship among expression of Bcl-2 family proteins, caspase activation, and ceramide formation has not yet been understood. Therefore, we have attempted to examine their sequential relation in the etoposide-induced glial apoptosis. Subsequently, in the first paper, we have demonstrated that ceramide induces change of the Bax/Bcl-2 ratio, which regulates cytochrome c release from mitochondria, leading to activat … More ion of caspase-9/-3 cascade. Moreover, in the second paper, we further examined the effects of Bcl-2, Bcl-xL, or Bax on the ceramide-mediated apoptotic pathways were examined in glioma cells overexpressing Bcl-2 or Bax. In conclusion, we have shown that Bax promotes apoptosis regardless of ceramide formation and that Bcl-2 or Bcl-xL prevents ceramide formation by repressing neutral sphingomyelinase as well as ceramide-induced cytochrome c release. However, the mechanism of ceramide formation, in other words, the activation of N-SMase by a DNA-damaging agent, etoposide is poorly understood. Therefore, in the third paper, we have examined the functional relationship between p53 and ceramide, and also tested the intermediary roles of ROS between them. Subsequently, we have revealed that p53 modulates intracellular ceramide levels through the formation of ROS in apoptotic human glioma cells. Further investigations regarding the ceramide pathway, especially identification of the upstream and downstream components of the sphingomyelin-ceramide signaling pathway, will lead to better understanding of the molecular mechanism of apoptosis induced by chemotherapeutic agents, and give us a novel approach for the treatment of malignant gliomas. Less