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

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

C2 - 24091621

SN - 1532-1827

VL - 109

SP - 2432=2444

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - October

ER -