| Targeting aberrant PI3K/Akt activation by PI103 restores sensitivity to TRAIL-induced apoptosis in neuroblastoma. | |
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MedLine Citation:
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PMID: 21355080 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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PURPOSE: Since we recently identified Akt activation as a novel poor prognostic indicator in neuroblastoma, we investigated whether 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 protein 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, while Mcl-1 silencing potentiates apoptosis. Bcl-2 overexpression also inhibits cleavage of caspase-3, -8 and Bid pointing to a mitochondria-driven feedback amplification loop.CONCLUSIONS: PI103 primes neuroblastoma cells for TRAIL-induced apoptosis by shifting the balance towards 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. |
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Authors:
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Daniela Opel; Ivonne Naumann; Maxi Schneider; Daniela Bertele; Klaus-Michael Debatin; Simone Fulda |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-2-25 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: - ISSN: 1078-0432 ISO Abbreviation: - Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-2-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Children's Hospital, University of Ulm. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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