Profiling Anti-Apoptotic BCL-xL Protein Expression in Glioblastoma Tumorspheres

SIMPLE SUMMARY: Glioblastoma is a fast-growing and very aggressive brain tumor. Its treatment is usually based on radiation and chemotherapy, which are inefficient owing to glioblastoma stem cells. Indeed, these cells are often resistant to therapy and are a source of tumor regrowth. Therefore, understanding how the survival of glioblastoma stem cells is regulated might unlock new therapeutic opportunities. We show here that certain glioblastoma cells, grown in specific conditions to favor glioblastoma stem cell proliferation, have a higher expression of BCL-xL, a protein preventing cancer cell death. This dependency on BCL-xL can be therapeutically targeted with specific BH3 mimetics drugs, designed to inhibit BCL-xL and thus induce efficient glioblastoma cell death. Overall, our study advocates for a better understanding of how to specifically target BCL-xL to trigger glioblastoma cell death. ABSTRACT: Glioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells (GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or radiotherapy. In this study, we investigate the expression pattern of the anti-apoptotic BCL-xL protein in several GBM cell lines and the role it might play in GSC-enriched tumorspheres. We report that several GBM cell lines have an increased BCL-xL expression in tumorspheres compared to differentiated cells. Moreover, by artificially modulating BCL-xL expression, we unravel a correlation between BCL-xL and tumorsphere size. In addition, BCL-xL upregulation appears to sensitize GBM tumorspheres to newly developed BH3 mimetics, opening promising therapeutic perspectives for treating GBM patients.