Inhibitor of apoptosis proteins determine glioblastoma stem-like cells fate depending on oxygen level

Souberan, A.; Cappai, J.; Chocry, M.; Nuccio, C.; Raujol, J.; Colin, C.; Lafitte, D.; Kovacic, H.; Quillien, V.; Baeza-Kallee, N.; Rougon, G.; Figarella-Branger, D.; Tchoghandjian, A.

doi:10.1101/259283

bioRxiv · 10.1101/259283

Inhibitor of apoptosis proteins determine glioblastoma stem-like cells fate depending on oxygen level

Souberan, A.·Cappai, J.·Chocry, M.·Nuccio, C.·Raujol, J.·Colin, C.·Lafitte, D.·Kovacic, H.·Quillien, V.·Baeza-Kallee, N.·Rougon, G.·Figarella-Branger, D.·Tchoghandjian, A.

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Abstract

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-{kappa}B. 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.

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Souberan, A., Cappai, J., Chocry, M., Nuccio, C., Raujol, J., Colin, C., Lafitte, D., Kovacic, H., Quillien, V., Baeza-Kallee, N., Rougon, G., Figarella-Branger, D., Tchoghandjian, A.. 2018-02-02. Inhibitor of apoptosis proteins determine glioblastoma stem-like cells fate depending on oxygen level. https://doi.org/10.1101/259283

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