Inhibitor of Apoptosis Proteins Determine Glioblastoma Stem‐Like Cells Fate in an Oxygen‐Dependent Manner

In glioblastomas, apoptosis inhibitor proteins(IAPs) are involved in apoptotic and non-apoptotic processes. We previously showed that IAPs inhibition induced a loss of stemness and glioblastomastem cells differentiation by activating nuclear factor-κB under normoxic conditions. Hypoxia has been shown to modulate drug efficacy. Here, we investigated how IAPs participate in glioblastomastem-like cell maintenance and fate under hypoxia. We showed that in a hypoxic environment, IAPs inhibition by GDC-0152, a small-molecule IAPs inhibitor, triggered stem-like cell apoptosis and decreased proliferation in four human glioblastomacell lines. We set up a three-dimensional glioblastomaspheroid model in which time-of-flight secondary ion mass spectrometry analyses revealed a decrease in oxygen levels between the periphery and core. We observed low proliferative and apoptotic cells located close to the hypoxic core of the spheres and glial fibrillary acidic protein+ cells at their periphery. These oxygen-dependent GDC-0152 antitumoral effects have been confirmed on human glioblastomaexplants. Notably, serine-threonine kinase activation analysis revealed that under hypoxic conditions, IAPs inhibition activated ataxia telangiectasiaand Rad3-relatedprotein signaling. Our findings provide new insights into the dual mechanism of action of IAPs inhibitors that depends on oxygen level and are relevant to their therapeutic application in tumors. Stem Cells 2019.