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Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells

Oncogene volume 29, pages 3276–3286 (2010)Cite this article

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Abstract

The use of c-abl-specific inhibitors such as Imatinib (IM) or Dasatinib has revolutionized the treatment of chronic myeloid leukemia (CML). However, a significant percentage of patients become resistant to IM. In this report, we have analyzed the possibility of using the proteasome as a molecular target in CML. Our results show that cells that express Bcr-Abl1 are more sensitive to the inhibition of the proteasome with Bortezomib (Btz) than control cells. This treatment reduces the proliferation of Bcr-Abl1-expressing cells, by inactivating NF-κB2 and decreasing the phosphorylation of Rb, eventually leading to an increase in caspase-dependent apoptosis. Furthermore, we show that Btz also induces cell-cycle arrest and apoptosis in cells expressing Bcr-Abl1 mutants that are resistant to IM. These results unravel a new molecular target of Btz, that is the Rb pathway, and open new possibilities in the treatment of CML especially for patients that become resistant to IM because of the presence of the T315I mutation.

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Acknowledgements

We thank Dr Elisabeth Buchdunger at Novartis for providing us with Imatinib and Millenium Pharmaceuticals for the kind gift of Bortezomib. We also thank Dr BJ Druker for the mutant Bcr-Abl1-expressing BaF/3 cells. The study was supported by grants from the Instituto de Salud Carlos III PI060285, PI070602 and RD06/0020 to IPR, FP and EJA; from the Consellería de Sanitat to IPR; from the Cardenal Herrera-CEU University (PRUCH and Santander-Copernicus) to IPR and ‘UTE project CIMA’. Fellowships were from the Cardenal Herrera-CEU University to MPA and JJV and from the Generalitat Valenciana to JMV. EJA is supported by the program Ramon y Cajal from the Ministerio de Ciencia e Innovación.

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Authors and Affiliations

  1. Department of Chemistry, Biochemistry and Molecular Biology, Cardenal Herrera-CEU University, Moncada, Spain

    M P Albero, J M Vaquer, J J Villanueva, L Franch, C Ivorra, E Poch & I Pérez-Roger

  2. Hematology Department and Area of Cell Therapy, Clinica Universidad de Navarra, Foundation for Applied Medical Research University of Navarra, Pamplona, Spain

    E J Andreu, X Agirre & F Prosper

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  1. M P Albero
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Correspondence to I Pérez-Roger.

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Albero, M., Vaquer, J., Andreu, E. et al. Bortezomib decreases Rb phosphorylation and induces caspase-dependent apoptosis in Imatinib-sensitive and -resistant Bcr-Abl1-expressing cells. Oncogene 29, 3276–3286 (2010). https://doi.org/10.1038/onc.2010.81

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