Targeting Aberrant PI3K/Akt Activation by PI103 Restores Sensitivity to TRAIL-Induced Apoptosis in Neuroblastoma
| Autor: | Klaus-Michael Debatin, Maxi Schneider, Ivonne Naumann, Simone Fulda, Daniela Opel, Daniela Bertele |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
medicine.medical_specialty Programmed cell death Pyridines Apoptosis Chick Embryo Biology Caspase 8 TNF-Related Apoptosis-Inducing Ligand Mice Neuroblastoma Phosphatidylinositol 3-Kinases Internal medicine Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured medicine Animals Humans Molecular Targeted Therapy Furans Protein Kinase Inhibitors Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Gene knockdown Brain Neoplasms Drug Synergism medicine.disease Xenograft Model Antitumor Assays XIAP Enzyme Activation Pyrimidines Endocrinology Oncology Drug Resistance Neoplasm Mutation Cancer research Proto-Oncogene Proteins c-akt |
| Zdroj: | Clinical Cancer Research. 17:3233-3247 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-10-2530 |
| Popis: | Purpose: Because we recently identified Akt activation as a novel poor prognostic indicator in neuroblastoma, we investigated whether phosphoinositide 3′-kinase (PI3K) inhibition sensitizes neuroblastoma cells for TRAIL-induced apoptosis. Experimental Design: The effect of pharmacological or genetic inhibition of PI3K or mTOR was analyzed on apoptosis induction, clonogenic survival, and activation of apoptosis signaling pathways in vitro and in a neuroblastoma in vivo model. The functional relevance of individual Bcl-2 family proteins was examined by knockdown or overexpression experiments. Results: The PI3K inhibitor PI103 cooperates with TRAIL to synergistically induce apoptosis (combination index < 0.1), to suppress clonogenic survival, and to reduce tumor growth in a neuroblastoma in vivo model. Similarly, genetic silencing of PI3K significantly increases TRAIL-mediated apoptosis, whereas genetic or pharmacological blockage of mTOR fails to potentiate TRAIL-induced apoptosis. Combined treatment with PI103 and TRAIL enhances cleavage of Bid and the insertion of tBid into mitochondrial membranes, and reduces phosphorylation of BimEL. Additionally, PI103 decreases expression of Mcl-1, XIAP, and cFLIP, thereby promoting Bax/Bak activation, mitochondrial perturbations, and caspase-dependent apoptosis. Knockdown of Bid or Noxa or overexpression of Bcl-2 rescues cells from PI103- and TRAIL-induced apoptosis, whereas Mcl-1 silencing potentiates apoptosis. Bcl-2 overexpression also inhibits cleavage of caspase-3, caspase-8, and Bid pointing to a mitochondria-driven feedback amplification loop. Conclusions: PI103 primes neuroblastoma cells for TRAIL-induced apoptosis by shifting the balance toward proapoptotic Bcl-2 family members and increased mitochondrial apoptosis. Thus, PI3K inhibitors represent a novel promising approach to enhance the efficacy of TRAIL-based treatment protocols in neuroblastoma. Clin Cancer Res; 17(10); 3233–47. ©2011 AACR. |
| Databáze: | OpenAIRE |
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