Role of NAD‐dependent deacetylases <i>SIRT1</i> and <i>SIRT2</i> in radiation and cisplatin‐induced cell death in vertebrate cells

Matsushita, Nobuko; Yasuda, Takami; Kimura, Masayo; Tachiiri, Seiji; Ishiai, Masamichi; Nakayama, Takeo; Takata, Minoru

doi:10.1111/j.1365-2443.2005.00836.x

Cited by 92 publications

(74 citation statements)

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“…It was reported that SIRT1 upregulates the expression of multidrug resistance 1 (MDR1) in cancer, and this may cause cancer resistance to chemotherapy (16). SIRT1-deficient cells exhibited p53 hyperacetylation following DNA damage and increased ionizing radiation-induced thymocyte apoptosis in vivo along with downregulation of MDR1 (16)(17)(18)(19). This evidence indicates the oncogenic role of SIRT1.…”

Section: Introductionmentioning

confidence: 67%

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein

et al. 2013

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Abstract. Silent mating-type information regulation 2 homologue 1 (SIRT1), a member of the class III histone deacetylase (HDAC) family, is the mammalian ortholog of yeast Sir2. It has been reported to play a key role in a variety of physiological processes such as genomic stability, metabolism, neurogenesis and cell survival. The deacetylase function of SIRT1 has been suggested to play a role in prolonging the life of mammals. However, the suggested functions of SIRT1 as a potential tumor promoter have been challenged by observations of their respective downregulation and upregulation in various types of cancer. Breast cancer patients were included in the present study between 2007 and 2008. Their tumor tissues and paired normal breast tissues were collected and used for evaluation of the expression levels of SIRT1 and Ki67. The effects of SIRT1 on human breast cancer cell lines were also investigated. Immunohistochemistry showed that there is a high correlation between SIRT1 and Ki67 expression. Following treatment with sirtinol (inhibitor of SIRT1), the expression of the prosurvival protein Bcl-2 was markedly decreased in both MCF-7 and MDA-MB-231 cell lines, particularly in MDA-MB-231. Results of the present study revealed that inhibition of SIRT1 activity may be a promising chemotherapeutic strategy against breast cancer.

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Section: Introductionmentioning

confidence: 67%

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein

et al. 2013

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“…7 Tumors with high levels of SIRT2 are refractory to chemotherapy. 38 In our study, SIRT2 was localized in both the cytoplasm and nucleus. Moreover, inhibition of SIRT2 induced cell-cycle arrest, leaving no cells in the G2/M phase with a significant reduction of cells in S phase.…”

Section: Discussionmentioning

confidence: 88%

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Liu¹,

Klimenkova²,

Klimiankou³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundInhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear. Design and MethodsHere, we evaluated whether nicotinamide phosphoribosyltransferase's effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process. ResultsWe identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation. ConclusionsOur results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation.

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“…These findings suggest that the tumor suppressor p53 is integral to the cytotoxic activity of the SIRT inhibitors Sirtinol and Salermide, and the failure of EX527 to trigger cell death is because of its inability to acetylate and activate the endogenous p53. A cooperative role for SIRT1 and SIRT2 to regulate stress-induced cell death pathways in a p53-independent manner has also been described (25). It is also likely that SIRT inhibitors, such as Sirtinol and Salermide, also target SIRTs other than SIRT1 and SIRT2.…”

Section: Discussionmentioning

confidence: 97%

“…In consequence, it has been proposed that SIRT2 might function as a mitotic checkpoint protein in G 2 -M to prevent the induction of chromosomal instability, particularly in response to microtubule inhibitor-mediated mitotic stress (24). Consistently, tumors with high levels of SIRT2 are refractory to chemotherapy, especially microtubule poisons (25).…”

Section: Introductionmentioning

confidence: 99%

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Peck

Chen

et al. 2010

Molecular Cancer Therapeutics

386

332

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SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 μmol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G 1 at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermideinduced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844-55. ©2010 AACR.

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Role of NAD‐dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin‐induced cell death in vertebrate cells

Cited by 92 publications

References 54 publications

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

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