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

    Research output: Contribution to journalArticle

    10 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

    Fingerprint

    Autophagy
    B-Cell Chronic Lymphocytic Leukemia
    Cell Cycle
    Sirtuins
    Apoptosis
    tenovin-6
    Proteasome Endopeptidase Complex
    Acetylation
    Ubiquitin
    Caspase 3
    Publications
    Cell Survival
    Electron Microscopy
    Leukemia
    Proteins
    Cell Death
    Up-Regulation
    Phenotype

    Cite this

    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. / p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia. In: British Journal of Cancer. 2013 ; Vol. 109, No. October. pp. 2432=2444.
    @article{5ff9cfe0bcd643ee9ea2c57c31e08b05,
    title = "p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia",
    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.",
    author = "Groves, {M J} and Johnson, {C E} and J James and Prescott, {A. R.} and J Cunningham and S Haydock and C Pepper and C Fegan and L Pirrie and Westwood, {N J} and Coates, {P. J.} and Ganley, {I. G.} and S. Tauro",
    year = "2013",
    doi = "10.1038/bjc.2013.601",
    language = "English",
    volume = "109",
    pages = "2432=2444",
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    Groves, MJ, Johnson, CE, James, J, Prescott, AR, Cunningham, J, Haydock, S, Pepper, C, Fegan, C, Pirrie, L, Westwood, NJ, Coates, PJ, Ganley, IG & Tauro, S 2013, 'p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia', British Journal of Cancer, vol. 109, no. October, pp. 2432=2444. https://doi.org/10.1038/bjc.2013.601

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

    In: British Journal of Cancer, Vol. 109, No. October, 2013, p. 2432=2444.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia

    AU - Groves, M J

    AU - Johnson, C E

    AU - James, J

    AU - Prescott, A. R.

    AU - Cunningham, J

    AU - Haydock, S

    AU - Pepper, C

    AU - Fegan, C

    AU - Pirrie, L

    AU - Westwood, N J

    AU - Coates, P. J.

    AU - Ganley, I. G.

    AU - Tauro, S.

    PY - 2013

    Y1 - 2013

    N2 - 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.

    AB - 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.

    U2 - 10.1038/bjc.2013.601

    DO - 10.1038/bjc.2013.601

    M3 - Article

    VL - 109

    SP - 2432=2444

    JO - British Journal of Cancer

    JF - British Journal of Cancer

    SN - 0007-0920

    IS - October

    ER -