TY - JOUR T1 - Inhibitor of apoptosis proteins determine glioblastoma stem-like cells fate depending on oxygen level JF - bioRxiv DO - 10.1101/259283 SP - 259283 AU - Aurélie Soubéran AU - Jessica Cappaï AU - Mathieu Chocry AU - Christopher Nuccio AU - Julie Raujol AU - Carole Colin AU - Daniel Lafitte AU - Hervé Kovacic AU - Véronique Quillien AU - Nathalie Baeza-Kallee AU - Geneviève Rougon AU - Dominique Figarella-Branger AU - Aurélie Tchoghandjian Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/02/02/259283.abstract N2 - In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and non-apoptotic processes. Here we used GDC-0152, a small molecule IAP inhibitor, to explore how IAPs participate in glioblastoma stem-like cell maintenance and fate under both hypoxic and normoxic environments. In hypoxia, IAPs inhibition triggered stem-like cells apoptosis and decreased proliferation in four human glioblastoma cell lines, whereas in normoxia it induced a loss of stemness and differentiation. In addition, we characterized a 3D glioblastoma spheroid model. By using MALDI images we validated that GDC-0152 penetrates in the entire sphere. TOF-SIMS analyses revealed an oxygen gradient correlated with spatial cellular heterogeneity with proliferative and apoptotic cells located close to the hypoxic core and GFAP+ cells at the periphery. Notably, Serine-Threonine Kinases activation analysis revealed that oxygen level affects signaling pathways activated by GDC-0152. In hypoxia, IAPs inhibition activated ATR whereas in normoxia it activated NF-κB. Our data brings new mechanistic insights revealing the dual role of IAPs inhibitors like GDC-0152 that are relevant to their therapeutic application in tumors like glioblastomas. ER -