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 journalArticle

20 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

Fingerprint

Autophagy
B-Cell Chronic Lymphocytic Leukemia
tenovin-6
Hematopoiesis
Genes
Proteins
Apoptosis

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

Cite this

MacCallum, Stephanie F. ; Groves, M.J. ; James, J. ; Murray, K. ; Appleyard, Virginia ; Prescott, Alan R. ; Drbal, A.A. ; Nicolaou, A. ; Cunningham, Joan ; Haydock, S. ; Ganley, Ian G. ; Westwood, N.J. ; Coates, Philip J. ; Lain, Sonia ; Tauro, Sudhir. / Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6. In: Scientific Reports. 2013 ; Vol. 3.
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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.",
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author = "MacCallum, {Stephanie F.} and M.J. Groves and J. James and K. Murray and Virginia Appleyard and Prescott, {Alan R.} and A.A. Drbal and A. Nicolaou and Joan Cunningham and S. Haydock and Ganley, {Ian G.} and N.J. Westwood and Coates, {Philip J.} and Sonia Lain and Sudhir Tauro",
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MacCallum, SF, Groves, MJ, James, J, Murray, K, Appleyard, V, Prescott, AR, Drbal, AA, Nicolaou, A, Cunningham, J, Haydock, S, Ganley, IG, Westwood, NJ, Coates, PJ, 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

Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6. / MacCallum, Stephanie F.; Groves, M.J.; James, J.; Murray, K.; Appleyard, Virginia; Prescott, Alan R.; Drbal, A.A.; Nicolaou, A.; Cunningham, Joan; Haydock, S.; Ganley, Ian G.; Westwood, N.J.; Coates, Philip J.; Lain, Sonia; Tauro, Sudhir.

In: Scientific Reports, Vol. 3, 1275, 2013.

Research output: Contribution to journalArticle

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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.

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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

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