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Imatinib enhances human melanoma cell susceptibility to TRAIL-induced cell death: relationship to Bcl-2 family and caspase activation

Oncogene volume 25, pages 7618–7634 (2006)Cite this article

An Erratum to this article was published on 22 February 2007

Abstract

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 α-converting enzyme-like inhibitory protein (c-FLIP)L/S, Fas-associated DD kinase, p53, p21WAF1, 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, PDGFRα and PDGFRβ, but it did affect the expression of c-FLIPL, BCL2-associated X protein (Bax) and Bcl-2. Moreover, c-FLIPL 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-FLIPL recruitment to the DISC and the inhibition of caspase 8, 3 and 9 processing. Moreover, c-FLIPL knockdown partly restored TRAIL sensitivity in G1 cells, indicating that the expression level of c-FLIPL 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-XL ratio, Bax:Bcl-XL/Bcl-2 translocation, cytochrome c release and caspase activation. Our data indicate that imatinib sensitizes T1 cells by directly downregulating c-FLIPL, with the use of an alternative pathway for antitumor activity, because PDGFRα is not activated in T1 cells and these cells do not express c-kit, c-ABL or PDGFRβ. Caspase cascade activation and mitochondria also play a key role in the imatinib-mediated sensitization of melanoma cells to the proapoptotic action of TRAIL.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

Bax:

BCL2-associated X protein

Bcl-2:

B-cell leukemia/lymphoma 2

Bcl-XL/BCL2L1:

BCL2-like 1

Bid:

BH3-interacting domain death agonist

DcR:

decoy receptor

DISC:

death-inducing signaling complex

DR:

death receptor

FADD:

Fas-associated DD kinase

FLICE:

FADD-like interleukin-1 α-converting enzyme

c-FLIP:

cellular FLICE-like inhibitory protein

IC50:

concentration giving 50% growth inhibition

Δψm:

mitochondrial transmembrane potential

PARP:

poly-ADP-ribose polymerase

PCA:

principal component analysis

PDGFRs:

platelet-derived growth factor receptors

PI:

propidium iodide

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

TRAIL-R:

TRAIL receptor

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Acknowledgements

We thank Philippe Dessen for his continuous help with microarray data analysis, Nazanine Modjtahedi for helpful discussions, Marie-Dominique Galibert for reading the manuscript and Catherine Gaudin and Thomas Robert for technical assistance. This work was supported by grants from INSERM, Association pour la Recherche sur le Cancer (grant 3520 to MD), and Ligue Nationale Contre le Cancer (Val de Marne 2002). Ahmed Hamaï is a recipient of a fellowship from cancéropole Ile de France and Fondation de France.

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Authors and Affiliations

  1. INSERM, U753, Laboratoire d’Immunologie des Tumeurs Humaines: Interaction effecteurs cytotoxiques-système tumoral, Institut Gustave Roussy PR1 and IFR 54, Villejuif, France

    A Hamaï, C Richon, F Meslin, A Jalil, S Chouaib & M Mehrpour

  2. INSERM, U520, laboratoire de biologie cellulaire de l’immunité antitumorale, Institut Curie, Paris, France

    F Faure

  3. CNRS, UMR 8125, laboratoire de Génétique Oncologique, Institut Gustave Roussy PR1, Villejuif, France

    A Kauffmann

  4. Institut Gustave Roussy PR2, Villejuif, France

    Y Lecluse & M F Avril

  5. CNRS, UMR 146, Génétique du développement des mélanocytes, Institut Curie, Orsay, France

    L Larue

  6. Chinese Academy of Sciences, Laboratory of Apoptosis and Cancer Biology, The National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Beijing, China

    M Mehrpour

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  1. A Hamaï
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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Hamaï, A., Richon, C., Meslin, F. et al. Imatinib enhances human melanoma cell susceptibility to TRAIL-induced cell death: relationship to Bcl-2 family and caspase activation. Oncogene 25, 7618–7634 (2006). https://doi.org/10.1038/sj.onc.1209738

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