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

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 beta-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.

• Authors: H Ota, E Tokunaga, K Chang, M Hikasa, K Iijima, M Eto, K Kozaki, M Akishita, Y Ouchi, M Kaneki
• Journal: Oncogene (Oncogene) Vol. 25 Issue 2 Pg. 176-85 (Jan 12 2006) ISSN: 0950-9232 [Print] England
• PMID: 16170353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• Naphthols
• Plasminogen Activator Inhibitor 1
• sirtinol
• Tyrosine
• Epidermal Growth Factor
• Insulin-Like Growth Factor I
• Phosphatidylinositol 3-Kinases
• ErbB Receptors
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• beta-Galactosidase
• SIRT1 protein, human
• Sirtuin 1
• Sirtuins

Topics

• Benzamides (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cellular Senescence (drug effects)
• Enzyme Activation (drug effects)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (metabolism)
• Genes, ras (physiology)
• Histone Deacetylase Inhibitors
• Humans
• Insulin-Like Growth Factor I (pharmacology)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Naphthols (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Plasminogen Activator Inhibitor 1 (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, IGF Type 1 (metabolism)
• Signal Transduction (drug effects)
• Sirtuin 1
• Sirtuins (antagonists & inhibitors)
• Tumor Cells, Cultured
• Tyrosine (metabolism)
• beta-Galactosidase (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)