Document Detail

Imatinib enhances human melanoma cell susceptibility to TRAIL-induced cell death: Relationship to Bcl-2 family and caspase activation.
MedLine Citation:
PMID:  16983347     Owner:  NLM     Status:  MEDLINE    
In order to define genetic determinants of primary and metastatic melanoma cell susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we have applied oligonucleotide microarrays to TRAIL-sensitive primary T1 cells and TRAIL-resistant metastatic G1 cells treated or not with TRAIL. T1 and G1 cells are isogenic melanoma cell subclones. We examined 22 000 spots, 4.2% of which displayed differential expression in G1 and T1 cells. Cell susceptibility to TRAIL-mediated apoptosis was found to be correlated with gene expression signatures in this model. Some of the differentially expressed genes were identified as involved in ATP-binding and signaling pathways, based on previously published data. Further analysis provided evidences that c-kit was overexpressed in G1 cells while it was absent in T1 cells. The c-kit inhibitor, imatinib, did not restore TRAIL sensitivity, excluding a role for c-kit in TRAIL resistance in G1 cells. Surprisingly, imatinib inhibited cell proliferation and TRAIL-mediated apoptosis in melanoma cells. We investigated the possible involvement of several molecules, including c-ABL, platelet-derived growth factor receptor (PDGFR), cellular FADD-like interleukin-1 alpha-converting enzyme-like inhibitory protein (c-FLIP)(L/S), Fas-associated DD kinase, p53, p21(WAF1), proteins of B-cell leukemia/lymphoma 2 (Bcl-2) family and cytochrome c. Imatinib did not modulate the expression or activation of its own targets, such as c-ABL, PDGFRalpha and PDGFRbeta, but it did affect the expression of c-FLIP(L), BCL2-associated X protein (Bax) and Bcl-2. Moreover, c-FLIP(L) knockdown sensitized T1 cells to TRAIL-mediated apoptosis, with a sensitivity similar to that of cells previously treated with imatinib. More notably, we found that the resistance to TRAIL in G1 cells was correlated with constitutive c-FLIP(L) recruitment to the DISC and the inhibition of caspase 8, 3 and 9 processing. Moreover, c-FLIP(L) knockdown partly restored TRAIL sensitivity in G1 cells, indicating that the expression level of c-FLIP(L) and its interaction with TRAIL receptor2 play a crucial role in determining TRAIL resistance in metastatic melanoma cells. Our results also show that imatinib enhances TRAIL-induced cell death independently of BH3-interacting domain death agonist translocation, in a process involving the Bax:Bcl-X(L) ratio, Bax:Bcl-X(L)/Bcl-2 translocation, cytochrome c release and caspase activation. Our data indicate that imatinib sensitizes T1 cells by directly downregulating c-FLIP(L), with the use of an alternative pathway for antitumor activity, because PDGFRalpha is not activated in T1 cells and these cells do not express c-kit, c-ABL or PDGFRbeta. Caspase cascade activation and mitochondria also play a key role in the imatinib-mediated sensitization of melanoma cells to the proapoptotic action of TRAIL.
A Hamaï; C Richon; F Meslin; F Faure; A Kauffmann; Y Lecluse; A Jalil; L Larue; M F Avril; S Chouaib; M Mehrpour
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-18
Journal Detail:
Title:  Oncogene     Volume:  25     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-12-07     Completed Date:  2007-01-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  7618-34     Citation Subset:  IM    
INSERM, U753, Laboratoire d'Immunologie des Tumeurs Humaines: Interaction effecteurs cytotoxiques-système tumoral, Institut Gustave Roussy PR1 and IFR 54, Villejuif, France.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Caspases / metabolism*
Cell Culture Techniques
Cell Line, Tumor
Cell Proliferation / drug effects
Enzyme Activation
Gene Expression Profiling
Melanoma / genetics,  metabolism,  pathology*
Neoplasm Metastasis / genetics,  pathology
Oligonucleotide Array Sequence Analysis
Piperazines / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Proto-Oncogene Proteins c-kit / metabolism
Pyrimidines / pharmacology*
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
Recombinant Proteins / pharmacology
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Reg. No./Substance:
0/Antineoplastic Agents; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrimidines; 0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/Recombinant Proteins; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 152459-95-5/imatinib; EC Proteins c-kit; EC 3.4.22.-/Caspases
Erratum In:
Oncogene. 2007 Feb 22;26(8):1256

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