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Chronic lymphocytic leukemia

Mitochondrial apoptosis is induced by Alkoxy phenyl-1-propanone derivatives through PP2A-mediated dephosphorylation of Bad and Foxo3A in CLL

Leukemia volume 33, pages 1148–1160 (2019)Cite this article

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Abstract

Protein phosphatase 2 A (PP2A) is a tumour suppressor whose strong inhibition underlies the phosphorylation-dependent, anti-apoptotic mechanisms in Chronic Lymphocytic Leukemia (CLL). Inactivation of PP2A is due to the cooperative action of the phosphorylation of Y307 of its catalytic subunit by the aberrant cytosolic pool of the Src Family Kinase Lyn and the interaction with its protein inhibitor SET, which is overexpressed in CLL. In this study, we developed a library of compounds, the most potent being the one named CC11, which restores PP2A activity by disrupting the PP2A/SET complex, thereby triggering the mitochondrial pathway of apoptosis. This process involves the recruitment of the pro-apoptotic BH3-only proteins Bad and Bim to mitochondria, the former upon direct dephosphorylation and the latter being newly expressed upon dephosphorylation and activation of its transcription factor FoxO3a. These findings highlight that PP2A antagonizes the prosurvival pathways controlled by Akt, which phosphorylates and thereby suppresses a variety of pro-apoptotic factors and tumour suppressors including Bad and FoxO3a. Furthermore, the PP2A-mediated pro-apoptotic effect of CC11 is synergistically potentiated by the abrogation of Lyn’s activity. Our results show that CC11 represents a promising lead compound for a new therapeutic rationale aimed at abrogating the aberrant oncogenic signals in CLL.

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Acknowledgements

This work was supported by funds from Ministero dell’Istruzione dell’Università e della Ricerca (PRIN 2010-2011 to L.T.), Associazione Italiana per la Ricerca sul Cancro AIRC (Milan) (AIRC project 15397), AIRC Regional Project with Fondazione CARIPARO and CARIVERONA, Regione Veneto on chronic lymphocytic leukaemia. V.T. is a fellowship from AIRC (Milan) (AIRC project 14972).

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Authors and Affiliations

  1. Department of Molecular Medicine, University of Padua, Padua, Italy

    Mario Angelo Pagano, Elena Tibaldi, Pierfrancesco Molino, Martina Frasson & Anna Maria Brunati

  2. Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy

    Federica Frezzato, Valentina Trimarco, Monica Facco, Andrea Visentin, Gianpietro Semenzato & Livio Trentin

  3. Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica Avanzata, Padua, Italy

    Federica Frezzato, Valentina Trimarco, Monica Facco, Andrea Visentin, Gianpietro Semenzato & Livio Trentin

  4. Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy

    Giuseppe Zagotto & Giovanni Ribaudo

  5. Department of Biology, University of Padua, Padua, Italy

    Luigi Leanza, Roberta Peruzzo & Ildikò Szabò

  6. CNR Institute of Neuroscience, Padova, Italy

    Ildikò Szabò

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Correspondence to Elena Tibaldi or Livio Trentin.

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A patent application related to the use of the alkoxy phenyl-1-propanone derivatives described in the present work has been filed on behalf of the University of Padua, Italy.

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Pagano, M.A., Tibaldi, E., Molino, P. et al. Mitochondrial apoptosis is induced by Alkoxy phenyl-1-propanone derivatives through PP2A-mediated dephosphorylation of Bad and Foxo3A in CLL. Leukemia 33, 1148–1160 (2019). https://doi.org/10.1038/s41375-018-0288-5

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