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West Ashley Library
9 a.m. – 7 p.m.
Phone: (843) 766-6635
Main Library
9 a.m. - 8 p.m.
Phone: (843) 805-6930
Folly Beach Library
Closed for renovations
Phone: (843) 588-2001
John L. Dart Library
9 a.m. – 7 p.m.
Phone: (843) 722-7550
St. Paul's/Hollywood Library
9 a.m. - 8 p.m.
Phone: (843) 889-3300
Mt. Pleasant Library
9 a.m. – 8 p.m.
Phone: (843) 849-6161
Dorchester Road Library
9 a.m. - 8 p.m.
Phone: (843) 552-6466
Edgar Allan Poe/Sullivan's Island Library
9 a.m. - 6 p.m.
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John's Island Library
9 a.m. – 8 p.m.
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McClellanville Library
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Edisto Library
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Wando Mount Pleasant Library
9 a.m. - 8 p.m.
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9 a.m. - 8 p.m.
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9 a.m. - 8 p.m.
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9 a.m. - 8 p.m.
Phone: (843) 805-6892
Village Library
9 a.m. - 6 p.m.
Phone: (843) 884-9741
Keith Summey North Charleston Library
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Phone: (843) 805-6909
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p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia.
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- Author(s): 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
- Source:
British Journal of Cancer; 10/29/2013, Vol. 109 Issue 9, p2434-2444, 11p- Subject Terms:
- Source:
- Additional Information
- 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 (P0.01), 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. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of British Journal of Cancer is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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