STEM-11MECHANISMS OF CDC20-ANAPHASE-PROMOTING COMPLEX ACTION IN HUMAN GLIOBLASTOMA STEM-LIKE CELLS

Abstract

Recent studies have shown that the major mitotic regulator CDC20-Anaphase Promoting Complex (APC) is required for the maintenance of human glioblastoma stem-like cells (GSCs), a clinically important subpopulation of glioblastoma cells that are believed to underlie tumor recurrence. We have previously shown that CDC20-APC operates through pluripotency transcription factor SOX2 to promote GSC self-renewal and invasion in vitro (Mao, Gujar et al. Cell Reports. 2015). Using patient-derived GSCs, we herein show that APC co-activator CDC20 is required for GSC tumorigenicity in an orthotopic xenograft model. We further demonstrate through in vivo epistasis experiments that CDC20 acts through SOX2 to control GSC tumorigenicity. To test if CDC20-APC activity might dictate GSC responsiveness to standard-of-care chemotherapy agent temozolomide (TMZ), we utilized pharmacological and genetic approaches to inhibit CDC20-APC activity. Intriguingly, both APC inhibitor ProTAME and lentiviral CDC20 RNA interference augmented TMZ cytotoxicity in human GSCs. Collectively, these data suggest that CDC20-APC controls the tumor-initiating potential of GSCs in vivo through SOX2 and that CDC20-APC inhibitory strategies may not only disrupt the GSC state but also enhance the efficacy of chemotherapy.