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

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

BCL-2 family proteins have mainly been studied as positive or negative regulators of apoptotic cell death (type I cell death). In glioblastomas, the BCL-2 and BCL-xL proteins contribute to an overall resistance to apoptosis which correlates with the clinically relevant chemo- and radioresistance. Our recent data demonstrate that BCL-xL specifically promotes the invasiveness of glioma cells in vitro and in vivo. This novel BCL-xL function is mediated by altered gene expression and does not depend on the direct anti-apoptotic effect of BCL-xL through sequestering pro-apoptotic BCL-2 family members. Moreover, BCL-2 and BCL-xL were recently described to be major regulators of autophagic cell death (type II cell death). There is increasing evidence that autophagy plays a crucial role in the tumorigenesis and therapy resistance of glioblastomas. Using molecular candidates identified in a NGFN2-funded project, the current subproject aims at characterizing the novel functions of BCL-2 and BCL-xL, invasiveness and autophagy, on a molecular level and at identifying targets that are clinically relevant to inhibit invasiveness and to promote autophagic cell death. Based on this knowledge, a clinical trial in newly diagnosed glioblastomas using temsirolimus (an autophagy-inducing drug) is planned.