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Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6
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dc.contributor.author | MacCallum, Stephanie F. | |
dc.contributor.author | Groves, Michael J. | |
dc.contributor.author | James, John | |
dc.contributor.author | Murray, Karen | |
dc.contributor.author | Appleyard, Virginia | |
dc.contributor.author | Prescott, Alan R. | |
dc.contributor.author | Drbal, Abed A. | |
dc.contributor.author | Nicolaou, Anna | |
dc.contributor.author | Cunningham, Joan | |
dc.contributor.author | Haydock, Sally | |
dc.contributor.author | Ganley, Ian G. | |
dc.contributor.author | Westwood, Nicholas J. | |
dc.contributor.author | Coates, Philip J. | |
dc.contributor.author | Lain, Sonia | |
dc.contributor.author | Tauro, Sudhir | |
dc.date.accessioned | 2014-07-21T11:01:06Z | |
dc.date.available | 2014-07-21T11:01:06Z | |
dc.date.issued | 2013-02-14 | |
dc.identifier | 134131875 | |
dc.identifier | 33b8fed0-471c-4e04-b240-a3401aef708d | |
dc.identifier | 000314864800003 | |
dc.identifier | 84874339014 | |
dc.identifier.citation | MacCallum , S F , Groves , M J , James , J , Murray , K , Appleyard , V , Prescott , A R , Drbal , A A , Nicolaou , A , Cunningham , J , Haydock , S , Ganley , I G , Westwood , N J , Coates , P J , Lain , S & Tauro , S 2013 , ' Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6 ' , Scientific Reports , vol. 3 , 1275 . https://doi.org/10.1038/srep01275 | en |
dc.identifier.issn | 2045-2322 | |
dc.identifier.other | ORCID: /0000-0003-0630-0138/work/56424165 | |
dc.identifier.uri | https://hdl.handle.net/10023/5043 | |
dc.description | The authors acknowledge TENOVUS Tayside for funding the study | en |
dc.description.abstract | Tenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways. | |
dc.format.extent | 8 | |
dc.format.extent | 1253117 | |
dc.language.iso | eng | |
dc.relation.ispartof | Scientific Reports | en |
dc.subject | Histone deacetylase | en |
dc.subject | Cell-death | en |
dc.subject | Electron-microscopy | en |
dc.subject | Promote longevity | en |
dc.subject | Stress response | en |
dc.subject | TP53 mutation | en |
dc.subject | In-vivo | en |
dc.subject | P53 | en |
dc.subject | Fludarabine | en |
dc.subject | Activation | en |
dc.subject | R Medicine | en |
dc.subject.lcc | R | en |
dc.title | Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6 | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. School of Chemistry | en |
dc.contributor.institution | University of St Andrews. EaSTCHEM | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.identifier.doi | 10.1038/srep01275 | |
dc.description.status | Peer reviewed | en |
dc.identifier.url | http://www.nature.com/srep/2013/130214/srep01275/extref/srep01275-s2.xls | en |
dc.identifier.url | http://www.nature.com/srep/2013/130214/srep01275/extref/srep01275-s1.pdf | en |
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