SIRT1 Negatively Regulates the Mammalian Target of Rapamycin

Roswell Park Cancer Institute, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2010; 5(2):e9199. DOI: 10.1371/journal.pone.0009199
Source: PubMed


The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.

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    • "Coupled with its role in inhibiting the protein synthesis in cancer cells [33, 34], controlling gluconeogenesis and glucose uptake and influencing insulin/ IGF-1 levels and signaling [31, 32], makes it an attractive contender mediating the antitumor effects of CR. AMPK and SIRT1 activation is a coordinated occurrence [35], where the downstream inhibition of mTOR is one of the major events [31, 36]. mTOR activation is implicated in almost every tumor type and the process of aging; both of which are slowed by CR, suggesting it to be the central molecule modulated during CR [37]. "
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    ABSTRACT: A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.
    Full-text · Article · Jul 2014 · Oncotarget
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    • "Furthermore, Ghosh et al. have demonstrated that SirT1 negatively regulates mTORC1 in mouse embryonic fibroblasts [22]: SirT1 associates with TSC2, and the interaction of SirT1 with TSC2 was demonstrated to be necessary for mTORC1 inhibition. Additionally, consistent with our present experiments, Ghosh et al. found a dose dependent effect of resveratrol on mTORC1 inhibition; Ghosh found that resveratrol treatment up to 25 µM stimulated SirT1 and negatively regulated the mTORC1 pathway, but high dose resveratrol treatment (100 µM), independent of SirT1, maintained mTORC1 inhibition. "
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    ABSTRACT: Phenotypic plasticity in vascular smooth muscle cells (VSMC) is necessary for vessel maintenance, repair and adaptation to vascular changes associated with aging. De-differentiated VSMC contribute to pathologies including atherosclerosis and intimal hyperplasia. As resveratrol has been reported to have cardio- protective effects, we investigated its role in VSMC phenotypic modulation. We demonstrated the novel finding that resveratrol promoted VSMC differentiation as measured by contractile protein expression, contractile morphology and contraction in collagen gels. Resveratrol induced VSMC differentiation through stimulation of SirT1 and AMPK. We made the novel finding that low or high dose resveratrol had an initially different mechanism on induction of differentiation. We found that low dose resveratrol stimulated differentiation through SirT1-mediated activation of AKT, whereas high dose resveratrol stimulated differentiation through AMPK-mediated inhibition of the mTORC1 pathway, allowing activation of AKT. The health effects of resveratrol in cardiovascular diseases, cancer and longevity are an area of active research. We have demonstrated a supplemental avenue where-by resveratrol may promote health by maintaining and enhancing plasticity of the vasculature.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "It forms two complexes, which are called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). SIRT1 could regulate mTOR signaling, and SIRT1 activation by resveratrol was found to down regulate mTOR signaling in HeLa cells and MEFs cells (Ghosh et al., 2010). The mechanism of hepatic steatosis has been not clearly elucidated , and previous studies indicated that the disorder of lipids metabolism is one of key reasons. "
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    ABSTRACT: Our result showed in the fatty liver formation induced-by overfeeding goose, it was accompanied by an activation of mammalian target of rapamycin (mTOR) pathway and cell proliferation. Recent studies have suggested a crucial role for mammalian sirtuin 1 (SIRT1) in regulating lipid metabolism and cell proliferation, so we hypothesize that resveratrol -activated and nicotinamide -inhibited SIRT1 acts goose hepatocellular lipid metabolism and cell proliferation by mTOR signal pathway. Here we show that both resveratrol and nicotinamide could evidently affect the DNA synthesis rate, the lipids accumulation, the mRNA level and protein content of genes involved in the lipids metabolism, mTOR signal pathway, and the cell cycle progression of goose primary hepatocytes. Moreover, rapamycin decreased the effect of nicotinamide on lipids accumulation and cell proliferation. These findings suggest that SIRT1 functions as a regulator for mTOR signaling and plays an essential role in the regulation of hepatocyte lipid metabolism and cell proliferation.
    Full-text · Article · Oct 2013 · Molecular and Cellular Endocrinology
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