Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6

Stephanie F. MacCallum, M.J. Groves, J. James, K. Murray, Virginia Appleyard, Alan R. Prescott, A.A. Drbal, A. Nicolaou, Joan Cunningham, S. Haydock, Ian G. Ganley, N.J. Westwood, Philip J. Coates, Sonia Lain, Sudhir Tauro

    Research output: Contribution to journalArticlepeer-review

    25 Citations (Scopus)

    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.
    Original languageEnglish
    Article number1275
    JournalScientific Reports
    Volume3
    DOIs
    Publication statusPublished - 2013

    Keywords

    • Aged
    • Animals
    • Autophagy
    • Benzamides
    • Cells, Cultured
    • Gene Expression Profiling
    • Hematopoietic Stem Cells
    • Humans
    • Leukemia, Lymphocytic, Chronic, B-Cell
    • Lysosomes
    • Macrolides
    • Mice
    • Microtubule-Associated Proteins
    • Middle Aged
    • Neoplastic Stem Cells
    • Sirtuins
    • Tumor Suppressor Protein p53

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