Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6
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.
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
Publication
Scientific Reports
Status
Peer reviewed
ISSN
2045-2322Type
Journal article
Description
The authors acknowledge TENOVUS Tayside for funding the studyCollections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.