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

Groves, M., Johnson, Charlotte ORCID: https://orcid.org/0000-0003-1954-5142, James, J., Prescott, A., Cunningham, J., Haydock, S., Pepper, Christopher John, Fegan, Christopher Daniel ORCID: https://orcid.org/0000-0001-9685-0621, 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:	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:	16 Nov 2022 07:22
URI:	https://orca.cardiff.ac.uk/id/eprint/75616

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