Nutrient Availability Regulates SIRT1 Through a Forkhead-Dependent Pathway

Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 01/2005; 306(5704):2105-8. DOI: 10.1126/science.1101731
Source: PubMed

ABSTRACT Nutrient availability regulates life-span in a wide range of organisms. We demonstrate that in mammalian cells, acute nutrient
withdrawal simultaneously augments expression of the SIRT1 deacetylase and activates the Forkhead transcription factor Foxo3a.
Knockdown of Foxo3a expression inhibited the starvation-induced increase in SIRT1 expression. Stimulation of SIRT1 transcription
by Foxo3a was mediated through two p53 binding sites present in the SIRT1 promoter, and a nutrient-sensitive physical interaction
was observed between Foxo3a and p53. SIRT1 expression was not induced in starved p53-deficient mice. Thus, in mammalian cells,
p53, Foxo3a, and SIRT1, three proteins separately implicated in aging, constitute a nutrient-sensing pathway.

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    • "Silent mating type information regulation 2 homolog 1 (SIRT1) belongs to the class III histone deacetylase (HDAC) family. Best known as a regulator in stress signaling, [1] [2] SIRT1 also exerts control on tumor suppressor genes, [3] [4] and influences lifespan in many organism [5] [6] [7]. In both cell lines and tumor specimens from diverse malignancies, SIRT1 is highly expressed [8] and evidence for epigenetic modification of SIRT1 suggests it may contribute to emergence of drug resistance in cancer [9] [10]. "
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    ABSTRACT: Psammaplin A (PsA) is a natural product isolated from marine sponges, which has been demonstrated to have anticancer activity against several human cancer cell lines via the induction of cell cycle arrest and apoptosis. New drugs that are less toxic and more effective against multidrug-resistant cancers are urgently needed. We tested cell proliferation, cell cycle progression and autophagic cell death pathway in doxorubicin-resistant MCF-7 (MCF-7/adr) human breast cancer cells. The potency of PsA was further determined using an in vivo xenograft model. PsA significantly inhibited MCF-7/adr cells proliferation in a concentration-dependent manner, with accumulation of cells in G2/M phase of the cell cycle. PsA significantly decreased SIRT1 enzyme activity and reduced expression of SIRT1 protein in the cultured cells with greater potency than sirtinol or salermide. Acetylation of p53, a putative target of SIRT1, increased significantly following PsA treatment. In addition, PsA markedly increased the expression levels of autophagy-related proteins. In support of this, it was found that PsA significantly increased the expression of damage-regulated autophagy modulator (DRAM), a p53-induced protein. The results of this study suggest that PsA is sufficient to overcome multidrug-resistant cancer via SIRT1-mediated autophagy in MCF-7/adr breast cancer cells, indicating that PsA has therapeutic potential for clinical use. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - General Subjects 11/2014; 1850(2):401-410. DOI:10.1016/j.bbagen.2014.11.007 · 4.38 Impact Factor
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    • "Sirt1 was reported to deacetylate various nonhistone protein targets, including p53, NF-κB, β-catenin, and FoxO3a [32–34]. Because H1299 cells do not express the tumor suppressor p53 protein, we used Western blot to analyze the protein level of β-catenin, NF-κB p65, and FoxO3a after sirtinol treatment (Figure 5). "
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    ABSTRACT: Sirtuins, NAD(+)-dependent deacetylases, could target both histones and nonhistone proteins in mammalian cells. Sirt1 is the major sirtuin and has been shown to involve various cellular processes, including antiapoptosis, cellular senescence. Sirt1 was reported to be overexpressed in many cancers, including lung cancer. Sirtinol, a specific inhibitor of Sirt1, has been shown to induce apoptosis of cancer cells by elevating endogenous level of reactive oxygen species. In the study, we investigated the effect of sirtinol on the proliferation and apoptosis of nonsmall cell lung cancer (NSCLC) H1299 cells. The results of proliferation assay and colony formation assay showed the antigrowth effect of sirtinol. The annexin-V staining further confirmed the apoptosis induction by sirtinol treatment. Interestingly, the levels of phosphorylated Akt and β-catenin were significantly downregulated with treating the apoptotic inducing doses. On the contrary, sirtinol treatment causes the significantly increased level of FoxO3a, a proapoptotic transcription factor targeted by Sirt1. These above results suggested that sirtinol may inhibit cell proliferation of H1299 cells by regulating the axis of Akt-β-catenin-FoxO3a. Overall, this study demonstrates that sirtinol attenuates the proliferation and induces apoptosis of NSCLC cells, indicating the potential treatment against NSCLC cells by inhibiting Sirt1 in future applications.
    08/2014; 2014:937051. DOI:10.1155/2014/937051
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    • "FOXO3 is a member of the human Forkhead-box (FOX) gene family that is known to have the distinct Forkhead DNA binding domain (13). As a transcriptional factor, FOXO3 is known to regulate various cellular processes such as cell cycle (14,15), cellular apoptosis (16–19), DNA damage repair (20,21), stress responses (15,22,23), metabolism (24), aging (25) and tumor suppression in mammalian cells (12,18,26). The results from gene knockout exhibit key functions of FOXO family members in tumor suppression (27) and in preventing the decline of the hematopoietic stem cell pool (28). "
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    ABSTRACT: Auranofin is a gold-containing compound classified by the World Health Organization as a clinically established rheumatoid arthritis therapeutic agent. Through drug screening for novel anticancer therapeutics, we unexpectedly identified auranofin as a potent anticancer agent against a p53-null ovarian carcinoma SKOV3 cell line. However, the molecular mechanism underlying auranofin-mediated anticancer activity in ovarian cancer cells is basically unknown. Here, we show that auranofin inhibits proliferation and survival of SKOV3 cells in a dose‑ and time‑dependent manner. Auranofin treatment activates the pro-apoptotic caspase-3, increases protein levels of apoptosis-inducing proteins Bax and Bim and reduces the expression of the anti-apoptotic mediator Bcl-2 in SKOV3 cells. Moreover, auranofin downregulates IκB kinase (IKK)-β and promotes nuclear localization and the activation of FOXO3 tumor suppressor, leading to cellular apoptosis in SKOV3 cells. In contrast, silencing FOXO3 diminishes the pro-apoptotic signaling of auranofin in SKOV3 cells. These results suggest that auranofin may induce caspase-3-mediated apoptosis in a FOXO3-dependent manner. The observed upregulation of pro-apoptotic genes and apoptosis in cancer cells without p53 in response to auranofin suggests a novel p53-independent mechanism underlying auranofin-induced apoptosis in ovarian cancer cells.
    International Journal of Oncology 08/2014; 45(4). DOI:10.3892/ijo.2014.2579 · 3.03 Impact Factor
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