1. Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner.
- Author
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Soubéran A, Cappaï J, Chocry M, Nuccio C, Raujol J, Colin C, Lafitte D, Kovacic H, Quillien V, Baeza-Kallee N, Rougon G, Figarella-Branger D, and Tchoghandjian A
- Subjects
- Adaptor Proteins, Signal Transducing antagonists & inhibitors, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adrenomedullin genetics, Adrenomedullin metabolism, Apoptosis drug effects, Baculoviral IAP Repeat-Containing 3 Protein antagonists & inhibitors, Baculoviral IAP Repeat-Containing 3 Protein genetics, Baculoviral IAP Repeat-Containing 3 Protein metabolism, Brain Neoplasms metabolism, Brain Neoplasms pathology, Carbonic Anhydrase IX genetics, Carbonic Anhydrase IX metabolism, Cell Differentiation drug effects, Cell Hypoxia genetics, Cell Line, Tumor, Cell Proliferation drug effects, Cyclohexanes pharmacology, Enzyme Inhibitors pharmacology, Glioblastoma metabolism, Glioblastoma pathology, Humans, Inhibitor of Apoptosis Proteins antagonists & inhibitors, Inhibitor of Apoptosis Proteins genetics, Inhibitor of Apoptosis Proteins metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Oxygen metabolism, Pyrroles pharmacology, Signal Transduction, Spheroids, Cellular drug effects, Spheroids, Cellular metabolism, Spheroids, Cellular pathology, Tissue Culture Techniques, X-Linked Inhibitor of Apoptosis Protein antagonists & inhibitors, X-Linked Inhibitor of Apoptosis Protein genetics, X-Linked Inhibitor of Apoptosis Protein metabolism, Apoptosis genetics, Brain Neoplasms genetics, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Neoplastic Stem Cells metabolism, Oxygen pharmacology
- Abstract
In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and nonapoptotic processes. We previously showed that IAP inhibition induced a loss of stemness and glioblastoma stem 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 glioblastoma stem-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 glioblastoma cell lines. We set up a three-dimensional glioblastoma spheroid 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 glioblastoma explants. Notably, serine-threonine kinase activation analysis revealed that under hypoxic conditions, IAP inhibition activated ataxia telangiectasia and Rad3-related protein signaling. Our findings provide new insights into the dual mechanism of action of IAP inhibitors that depends on oxygen level and are relevant to their therapeutic application in tumors. Stem Cells 2019;37:731-742., (©AlphaMed Press 2019.)- Published
- 2019
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