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

Groves, M., Johnson, Charlotte, James, J., Prescott, A., Cunningham, J., Haydock, S., Pepper, Christopher John, Fegan, Christopher Daniel, Pirrie, L., Westwood, N., Coates, P., Ganley, I. and Tauro, S. 2013. p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia. British Journal of Cancer 109 (9) , pp. 2434-2444. 10.1038/bjc.2013.601

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: apoptosis; autophagy; CLL; p53; tenovin-6
Publisher: Nature Publishing Group
ISSN: 0007-0920
Date of Acceptance: 11 September 2013
Last Modified: 23 Dec 2017 20:38
URI: http://orca.cf.ac.uk/id/eprint/75616

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