Document Detail


Autophagy inhibition cooperates with erlotinib to induce glioblastoma cell death.
MedLine Citation:
PMID:  21508666     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gliomas are the most common malignant primary brain tumors in adults. The median survival never exceeds 12 months, owing to inherent resistance to both radio and chemotherapies. Epidermal Growth Factor Receptor (EGFR) is amplified, overexpressed, and/or mutated in glioblastomas (GBM), making it a rational for therapy. Erlotinib, an EGFR kinase inhibitor is strongly associated with clinical response in several cancers. Inhibition of cell proliferation and induction of apoptosis by erlotinib were investigated in U87-MG and DBTRG-05MG, two human glioblastoma cell lines. The expression of several apoptosis-related proteins was investigated in these cell lines and in tumoral tissue from glioblastomas. Both cell lines expressed wild-type EGFR but were deficient for PTEN. Erlotinib induced a marked accumulation of the BIM protein, but the activation of caspase-3 machinery was missing, regardless of the decrease in XIAP. Moreover, in U87-MG, erlotinib promoted accumulation of αB-crystallin a small heat shock protein capable to impair caspase activation. DBTRG-05MG was found deficient for procaspase 3 and constitutively overexpressed αB-crystallin. Similarly, deficiencies in PTEN and procaspase 3 were constantly found in samples from glioblastoma samples, while αB-crystallin expression was inconsistent. In cell lines, high concentrations of erlotinib induced cell death through a caspase independent process and an autophagic process was evidenced in U87-MG. Inhibition of autophagy induced a marked increase in the death-inducing activity of erlotinib. These results confirm that glioblastoma cell lines exhibit several anti-apoptotic mechanisms, and underline that EGFR targeted therapy must be associated to other inhibitors to achieve an antitumoral effect.
Authors:
Sandrine Eimer; Marc-Antoine Belaud-Rotureau; Kelly Airiau; Marie Jeanneteau; Elodie Laharanne; Nadège Véron; Anne Vital; Hugues Loiseau; Jean-Philippe Merlio; Francis Belloc
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-06-15
Journal Detail:
Title:  Cancer biology & therapy     Volume:  11     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-16     Completed Date:  2011-10-06     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1017-27     Citation Subset:  IM    
Affiliation:
Histology and Molecular Pathology of Tumors Laboratory, Victor Segalen University, Bordeaux, France. sandrine.eimer@chu-bordeaux.fr
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism
Autophagy / drug effects*
Caspases / metabolism
Cell Line, Tumor
Glioblastoma / pathology*,  ultrastructure
HeLa Cells
Humans
Membrane Proteins / metabolism
Mitochondria / metabolism
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / metabolism
Quinazolines / pharmacology*
Receptor, Epidermal Growth Factor / antagonists & inhibitors
Signal Transduction / drug effects
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/Membrane Proteins; 0/Protein Kinase Inhibitors; 0/Proto-Oncogene Proteins; 0/Quinazolines; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.22.-/Caspases; J4T82NDH7E/erlotinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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