Novel functions of BCL-2 family proteins in glioblastomas: invasiveness and autophagy

Coordinator:		Dr. Wilfried Roth
Institution:		DKFZ Heidelberg
Homepage:		www.dkfz.de/apoptosis

Within this project, the functional relevance of the Bcl-2 and Bcl-xL proteins for autophagy – a form of cellular self digestion– has been analyzed. Initially, we could show that the extent of autophagy was not influenced by the expression levels of Bcl-2 and Bcl-xL, thereby demonstrating that autophagy is independent from Bcl-2 and Bcl-xL. This is a promising basis for targeting the anti-apoptotic proteins Bcl-2 and Bcl-xL in an experimental therapeutic approach. Such a new apoptosis-based therapy may be realized by the use of the Bcl-2/Bcl-xL inhibitor ABT-737. An important finding of this study was the characterization of the synergistic apoptotic effect of ABT-737 and radiation, which plays a pivotal role in the treatment of glioblastoma. Within this context we identified the tumor suppressor p53 as well as the anti-apoptotic protein Mcl-1 as factors negatively influencing the efficacy of the combination therapy. Therefore, the antitumorigenic effect of ABT-737 might be potentiated by a concomitant Mcl-1-antagonizing approach. Among others, the expression of Mcl-1 in glioblastoma cells is regulated by the Notch1 signaling pathway. Accordingly, the inhibition of Notch1 resulted in a decreased expression of Mcl-1 and thereby in an elevated sensitivity to ABT-737. Interestingly, glioblastoma cells were also sensitized to the death ligand mediated (extrinsic) apoptosis by the inactivation of Notch1. Hence, the repression of Notch1 signaling offers the possibility to both increase the apoptotic effect of ABT-737 and to overcome the resistance to extrinsic apoptosis of glioblastoma cells. Furthermore, a sensitization of tumor cells for extrinsic apoptosis is not only relevant in terms of an experimental therapeutic application of the death ligand TRAIL but also with regard to an efficient TRAIL-receptor mediated immunologic tumor defense. In summary, within this project the molecular connections between apoptosis and autophagy as well as the functional significance of the signaling pathways depending on Bcl-2 and Notch1 were further elucidated. The targeted initiation of apoptosis by Bcl-2-inhibitors or death ligands represents a promising therapeutic approach for the experimental treatment of brain tumors.