γ-Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down-regulation

Authors

  • Emanuela Rosati,

    Corresponding author
    1. Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy
    • Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, Via Enrico dal Pozzo, Padiglione-W, 06126, Perugia, Italy
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    • Tel.: +39-075-5855830, Fax: +39-075-5855827

  • Rita Sabatini,

    1. Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy
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  • Filomena De Falco,

    1. Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy
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    • R.S. and F.D.F. contributed equally to this study

  • Beatrice Del Papa,

    1. Department of Clinical and Experimental Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy
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  • Franca Falzetti,

    1. Department of Clinical and Experimental Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy
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  • Mauro Di Ianni,

    1. Department of Internal Medicine and Public Health, Chair of Hematology, University of L'Aquila, L'Aquila, Italy
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  • Laura Cavalli,

    1. Department of Clinical and Experimental Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy
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  • Katia Fettucciari,

    1. Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy
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  • Andrea Bartoli,

    1. Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy
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  • Isabella Screpanti,

    1. Department of Molecular Medicine, University La Sapienza, Rome, Italy
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  • Pierfrancesco Marconi

    1. Department of Clinical and Experimental Medicine, General Pathology and Immunology Section, University of Perugia, Perugia, Italy
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Errata

This article is corrected by:

  1. Errata: Erratum Volume 137, Issue 8, E17, Article first published online: 7 August 2015

Abstract

γ-Secretase inhibitors (GSIs) have been proposed for combined therapies of malignancies with a dysregulated Notch signaling. GSI I (Z-Leu-Leu-Nle-CHO) induces apoptosis of some tumor cells by inhibiting proteasome and Notch activity. Alterations in these two cell survival regulators contribute to apoptosis resistance of chronic lymphocytic leukemia (CLL) cells. Here, we investigated the mechanisms whereby GSI I increases apoptosis of primary CLL cells. Time-course studies indicate that initial apoptotic events are inhibition of proteasome activity, concomitant with an increased endoplasmic reticulum (ER) stress apoptotic signaling, and a consistent Noxa protein up-regulation. These events precede, and some of them contribute to, mitochondrial alterations, which occur notwithstanding Mcl-1 accumulation induced by GSI I. In CLL cells, GSI I inhibits Notch1 and Notch2 activation only in the late apoptotic phases, suggesting that this event does not initiate CLL cell apoptosis. However, Notch inhibition may contribute to amplify GSI I-induced CLL cell apoptosis, given that Notch activation sustains the survival of these cells, as demonstrated by the evidence that both Notch1 and Notch2 down-regulation by small-interfering RNA accelerates spontaneous CLL cell apoptosis. Overall, our results show that GSI I triggers CLL cell apoptosis by inhibiting proteasome activity and enhancing ER stress, and amplifies it by blocking Notch activation. These findings suggest the potential relevance of simultaneously targeting these three important apoptosis regulators as a novel therapeutic strategy for CLL.

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