title: 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.
authors: Dundee Cancer Centre, Ninewells Hospital, University of Dundee, Dundee, Scotland DD1 9SY, United Kingdom.
authors: Stephanie F
authors: SF
authors: MacCallum
authors: Michael J
authors: MJ
authors: Groves
authors: John
authors: J
authors: James
authors: Karen
authors: K
authors: Murray
authors: Virginia
authors: V
authors: Appleyard
authors: Alan R
authors: AR
authors: Prescott
authors: Abed A
authors: AA
authors: Drbal
authors: Anna
authors: A
authors: Nicolaou
authors: Joan
authors: J
authors: Cunningham
authors: Sally
authors: S
authors: Haydock
authors: Ian G
authors: IG
authors: Ganley
authors: Nicholas J
authors: NJ
authors: Westwood
authors: Philip J
authors: PJ
authors: Coates
authors: Sonia
authors: S
authors: Lain
authors: Sudhir
authors: S
authors: Tauro
mesh_terms: D000368:Aged; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000633:toxicity*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000633:toxicity; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D001549:Benzamides; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; C574854:tenovin-6; C040929:bafilomycin A1; D037761:Sirtuins