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Leukemia. 2019 May;33(5):1148-1160. doi: 10.1038/s41375-018-0288-5. Epub 2018 Oct 23.

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

Author information

1
Department of Molecular Medicine, University of Padua, Padua, Italy.
2
Department of Molecular Medicine, University of Padua, Padua, Italy. elena.tibaldi@unipd.it.
3
Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy.
4
Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica Avanzata, Padua, Italy.
5
Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
6
Department of Biology, University of Padua, Padua, Italy.
7
CNR Institute of Neuroscience, Padova, Italy.
8
Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy. livio.trentin@unipd.it.
9
Venetian Institute of Molecular Medicine, Centro di Eccellenza per la Ricerca Biomedica Avanzata, Padua, Italy. livio.trentin@unipd.it.

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.

PMID:
30353029
DOI:
10.1038/s41375-018-0288-5

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