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

TY - JOUR

T1 - Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6

AU - MacCallum, Stephanie F.

AU - Groves, M.J.

AU - James, J.

AU - Murray, K.

AU - Appleyard, Virginia

AU - Prescott, Alan R.

AU - Drbal, A.A.

AU - Nicolaou, A.

AU - Cunningham, Joan

AU - Haydock, S.

AU - Ganley, Ian G.

AU - Westwood, N.J.

AU - Coates, Philip J.

AU - Lain, Sonia

AU - Tauro, Sudhir

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Aged

KW - Animals

KW - Autophagy

KW - Benzamides

KW - Cells, Cultured

KW - Gene Expression Profiling

KW - Hematopoietic Stem Cells

KW - Humans

KW - Leukemia, Lymphocytic, Chronic, B-Cell

KW - Lysosomes

KW - Macrolides

KW - Mice

KW - Microtubule-Associated Proteins

KW - Middle Aged

KW - Neoplastic Stem Cells

KW - Sirtuins

KW - Tumor Suppressor Protein p53

UR - https://www.scopus.com/pages/publications/84874339014

U2 - 10.1038/srep01275

DO - 10.1038/srep01275

M3 - Article

C2 - 23429453

AN - SCOPUS:84874339014

SN - 2045-2322

VL - 3

JO - Scientific Reports

JF - Scientific Reports

M1 - 1275

ER -