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Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras–MAPK signaling in human cancer cells

Oncogene volume 25, pages 176–185 (2006)Cite this article

Abstract

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD+-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated β-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras–MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

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Acknowledgements

We thank Drs J Avruch and N Fujita for helpful discussion and the p27 cDNA probe, respectively. This work was supported by National Institute of Health (NIH) Grant R01DK058127 (MK).

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Authors and Affiliations

  1. Department of Anesthesia & Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    H Ota, E Tokunaga, K Chang, M Hikasa & M Kaneki

  2. Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan

    H Ota, K Iijima, M Eto, K Kozaki, M Akishita & Y Ouchi

  3. Shriners Hospital for Children, Boston, MA, USA

    E Tokunaga & M Kaneki

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  1. H Ota
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  2. E Tokunaga
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Correspondence to M Kaneki.

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Ota, H., Tokunaga, E., Chang, K. et al. Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras–MAPK signaling in human cancer cells. Oncogene 25, 176–185 (2006). https://doi.org/10.1038/sj.onc.1209049

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