DOI QR코드

DOI QR Code

Induction of Nuclear Enlargement and Senescence by Sirtuin Inhibitors in Glioblastoma Cells

  • Kyoung B. Yoon (College of Pharmacy and Research Institute of Life Sciences, Gyeongsang National University) ;
  • Kyeong R. Park (College of Pharmacy and Research Institute of Life Sciences, Gyeongsang National University) ;
  • Soo Y. Kim (Division of Basic Science, Research Institute, National Cancer Center) ;
  • Sun-Young Han (College of Pharmacy and Research Institute of Life Sciences, Gyeongsang National University)
  • Received : 2016.03.11
  • Accepted : 2016.05.20
  • Published : 2016.06.30

Abstract

Sirtuin family members with lysine deacetylase activity are known to play an important role in anti-aging and longevity. Cellular senescence is one of the hallmarks of aging, and downregulation of sirtuin is reported to induce premature senescence. In this study, we investigated the effects of small-molecule sirtuin inhibitors on cellular senescence. Various small molecules such as tenovin-1 and EX527 were employed for direct sirtuin activity inhibition. U251, SNB-75, and U87MG glioblastoma cells treated with sirtuin inhibitors exhibited phenotypes with nuclear enlargement. Furthermore, treatment of rat primary astrocytes with tenovin-1 also increased the size of the nucleus. The activity of senescence-associated β-galactosidase, a marker of cellular senescence, was induced by tenovin-1 and EX527 treatment in U87MG glioblastoma cells. Consistent with the senescent phenotype, treatment with tenovin-1 increased p53 expression in U87MG cells. This study demonstrated the senescence-inducing effect of sirtuin inhibitors, which are potentially useful tools for senescence research.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (2015R1C1A2A01053928), and by the Gyeongsang National University Fund for Professors on Sabbatical leave, 2016.

References

  1. Haigis, M. C., and D. A. Sinclair. 2010. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5: 253-295.
  2. Roth, M., and W. Y. Chen. 2014. Sorting out functions of sirtuins in cancer. Oncogene 33: 1609-1620.
  3. Lopez-Otin, C., M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer. 2013. The hallmarks of aging. Cell 153: 1194-1217.
  4. Campisi, J. 2013. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75: 685-705.
  5. Ghosh, S., and Z. Zhou. 2015. SIRTain regulators of premature senescence and accelerated aging. Protein Cell 6: 322-333.
  6. Menghini, R., V. Casagrande, M. Cardellini, E. Martelli, A. Terrinoni, F. Amati, M. Vasa-Nicotera, A. Ippoliti, G. Novelli, G. Melino, R. Lauro, and M. Federici. 2009. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation 120: 1524-1532.
  7. Stunkel, W., and R. M. Campbell. 2011. Sirtuin 1 (SIRT1): the misunderstood HDAC. J. Biomol. Screen. 16: 1153-1169.
  8. Carafa, V., A. Nebbioso, and L. Altucci. 2012. Sirtuins and disease: the road ahead. Front. Pharmacol. 3: 4.
  9. Napper, A. D., J. Hixon, T. McDonagh, K. Keavey, J. F. Pons, J. Barker, W. T. Yau, P. Amouzegh, A. Flegg, E. Hamelin, R. J. Thomas, M. Kates, S. Jones, M. A. Navia, J. O. Saunders, P. S. DiStefano, and R. Curtis. 2005. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J. Med. Chem. 48: 8045-8054.
  10. Mai, A., S. Massa, S. Lavu, R. Pezzi, S. Simeoni, R. Ragno, F. R. Mariotti, F. Chiani, G. Camilloni, and D. A. Sinclair. 2005. Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J. Med. Chem. 48: 7789-7795.
  11. Heltweg, B., T. Gatbonton, A. D. Schuler, J. Posakony, H. Li, S. Goehle, R. Kollipara, R. A. Depinho, Y. Gu, J. A. Simon, and A. Bedalov. 2006. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66: 4368-4377.
  12. Trapp, J., R. Meier, D. Hongwiset, M. U. Kassack, W. Sippl, and M. Jung. 2007. Structure-activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem 2: 1419-1431.
  13. Outeiro, T. F., E. Kontopoulos, S. M. Altmann, I. Kufareva, K. E. Strathearn, A. M. Amore, C. B. Volk, M. M. Maxwell, J. C. Rochet, P. J. McLean, A. B. Young, R. Abagyan, M. B. Feany, B. T. Hyman, and A. G. Kazantsev. 2007. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science 317: 516-519.
  14. Lain, S., J. J. Hollick, J. Campbell, O. D. Staples, M. Higgins, M. Aoubala, A. McCarthy, V. Appleyard, K. E. Murray, L. Baker, A. Thompson, J. Mathers, S. J. Holland, M. J. Stark, G. Pass, J. Woods, D. P. Lane, and N. J. Westwood. 2008. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13: 454-463.
  15. Lara, E., A. Mai, V. Calvanese, L. Altucci, P. Lopez-Nieva, M. L. Martinez-Chantar, M. Varela-Rey, D. Rotili, A. Nebbioso, S. Ropero, G. Montoya, J. Oyarzabal, S. Velasco, M. Serrano, M. Witt, A. Villar-Garea, A. Imhof, J. M. Mato, M. Esteller, and M. F. Fraga. 2009. Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene 28: 781-791.
  16. Kalle, A. M., A. Mallika, J. Badiger, Alinakhi, P. Talukdar, and Sachchidanand. 2010. Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells. Biochem. Biophys. Res. Commun. 401: 13-19.
  17. Zhang, Q., S. X. Zeng, Y. Zhang, Y. Zhang, D. Ding, Q. Ye, S. O. Meroueh, and H. Lu. 2012. A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53. EMBO Mol. Med. 4: 298-312.
  18. Choi, G., J. Lee, J. Y. Ji, J. Woo, N. S. Kang, S. Y. Cho, H. R. Kim, J. D. Ha, and S. Y. Han. 2013. Discovery of a potent small molecule SIRT1/2 inhibitor with anticancer effects. Int. J. Oncol. 43: 1205-1211.
  19. Mitsui, Y., and E. L. Schneider. 1976. Increased nuclear sizes in senescent human diploid fibroblast cultures. Exp. Cell Res. 100: 147-152.
  20. Kobayashi, Y., R. Sakemura, A. Kumagai, E. Sumikawa, M. Fujii, and D. Ayusawa. 2008. Nuclear swelling occurs during premature senescence mediated by MAP kinases in normal human fibroblasts. Biosci. Biotechnol. Biochem. 72: 1122-1125.
  21. North, B. J., B. L. Marshall, M. T. Borra, J. M. Denu, and E. Verdin. 2003. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11: 437-444.
  22. Sadaie, M., C. Dillon, M. Narita, A. R. Young, C. J. Cairney, L. S. Godwin, C. J. Torrance, D. C. Bennett, W. N. Keith, and M. Narita. 2015. Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition. Mol. Biol. Cell 26: 2971-2985.