p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia

M J Groves, C E Johnson, J James, A. R. Prescott, J Cunningham, S Haydock, C Pepper, C Fegan, L Pirrie, N J Westwood, P. J. Coates, I. G. Ganley, S. Tauro

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    11 Citations (Scopus)

    Abstract

    Background:Activation of wild-type p53 with the small molecule sirtuin inhibitor Tenovin-6 (Tnv-6) induces p53-dependent apoptosis in many malignant cells. In contrast, Tnv-6 reduces chronic lymphocytic leukaemia (CLL) cell viability with dysregulation of autophagy, without increasing p53-pathway activity.Methods:Here, we have investigated whether a quiescent phenotype (unique to CLL) determines the Tnv-6 response, by comparing the effects of Tnv-6 on activated and proliferating CLL. We further studied if these responses are p53-dependent.Results:Unlike quiescent cells, cell death in activated cultures treated with Tnv-6 was consistently associated with p53 upregulation. However, p53 acetylation remained unchanged, without caspase-3 cleavage or apoptosis on electron microscopy. Instead, cellular ultrastructure and protein profiles indicated autophagy inhibition, with reduced ubiquitin-proteasome activity. In specimens with mutant TP53 cultured with Tnv-6, changes in the autophagy-associated protein LC3 occurred independently of p53. Cells treated with Tnv-6 analogues lacking sirtuin inhibitory activity had attenuated LC3 lipidation compared with Tnv-6 (P?0.01), suggesting that autophagy dysregulation occurs predominantly through an effect on sirtuins.Conclusion:These cell cycle and p53-independent anti-leukaemic mechanisms potentially offer novel therapeutic approaches to target leukaemia-sustaining cells in CLL, including in disease with p53-pathway dysfunction. Whether targets in addition to sirtuins contribute to autophagy dysregulation by Tnv-6, requires further investigation.British Journal of Cancer advance online publication, 3 October 2013; doi:10.1038/bjc.2013.601 www.bjcancer.com.
    Original languageEnglish
    Pages (from-to)2432=2444
    Number of pages13
    JournalBritish Journal of Cancer
    Volume109
    Issue numberOctober
    DOIs
    Publication statusPublished - 2013

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    Groves, M. J., Johnson, C. E., James, J., Prescott, A. R., Cunningham, J., Haydock, S., Pepper, C., Fegan, C., Pirrie, L., Westwood, N. J., Coates, P. J., Ganley, I. G., & Tauro, S. (2013). p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia. British Journal of Cancer, 109(October), 2432=2444. https://doi.org/10.1038/bjc.2013.601