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      Resveratrol inhibits proliferation and migration through SIRT1 mediated post-translational modification of PI3K/AKT signaling in hepatocellular carcinoma cells

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          Abstract

          Resveratrol (RES), a polyphenolic compound present in grapes and red wine, has potential anticancer properties. The present study aimed to examine the effects of resveratrol and its underlying mechanism on hepatocellular carcinoma (HCC) cell lines HepG2, Bel-7402 and SMMC-7721. It was demonstrated that resveratrol inhibited the viability and proliferation of HCC cells assessed by MTT and EdU assays. TUNEL assay revealed that resveratrol induced cell apoptosis by increasing HCC apoptosis rate from 3±0.78% to 16±1.12% with upregulation of B-cell lymphoma (Bcl)-2 associated X, apoptosis regulator and cleaved-poly (ADP-Ribose) polymerase 1 (PARP), and downregulation of Bcl-2, caspase-3, caspase-7 and PARP. As a sirtuin (SIRT) 1 activator, resveratrol elevated SIRT1 protein expression and its enzyme activity and decreased expression levels of phosphorylated (p)-phosphoinositide-3-kinase (PI3K), p-AKT Serine/Threonine Kinase 1 (AKT), and its downstream target p-Forkhead Box O3a in HepG2 cells. Furthermore, inhibition of SIRT1 enzymatic activity by EX527 resulted in increased phosphorylation levels of PI3K and AKT. This demonstrated that resveratrol inhibited the PI3K/AKT pathway by SIRT1 activation. In addition to inhibition of cancer cell migration, tumor suppressor gene DLC1 Rho GTPase activating protein level was upregulated and its phosphorylation was enhanced by AKT with resveratrol treatment. These findings suggested that resveratrol inhibits proliferation and migration through SIRT1 mediated post-translational modification of PI3K/AKT pathway in HCC cells.

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          Most cited references 33

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          The Sir2 family of protein deacetylases.

          The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
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            FoxO transcription factors; Regulation by AKT and 14-3-3 proteins.

            The forkhead box O (FoxO) transcription factor family is a key player in an evolutionary conserved pathway downstream of insulin and insulin-like growth factor receptors. The mammalian FoxO family consists of FoxO1, 3, 4 and 6, which share high similarity in their structure, function and regulation. FoxO proteins are involved in diverse cellular and physiological processes including cell proliferation, apoptosis, reactive oxygen species (ROS) response, longevity, cancer and regulation of cell cycle and metabolism. The regulation of FoxO protein function involves an intricate network of posttranslational modifications and protein-protein interactions that provide integrated cellular response to changing physiological conditions and cues. AKT was identified in early genetic and biochemical studies as a main regulator of FoxO function in diverse organisms. Though other FoxO regulatory pathways and mechanisms have been delineated since, AKT remains a key regulator of the pathway. The present review summarizes the current knowledge of FoxO regulation by AKT and 14-3-3 proteins, focusing on its mechanistic and structural aspects and discusses its crosstalk with the other FoxO regulatory mechanisms. This article is part of a Special Issue entitled: PI3K-AKT-FoxO axis in cancer and aging. 2011 Elsevier B.V. All rights reserved.
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              FOXOs, cancer and regulation of apoptosis.

              Forkhead box O (FOXO) transcription factors are involved in multiple signaling pathways and play critical roles in a number of physiological and pathological processes including cancer. The importance of FOXO factors ascribes them under multiple levels of regulation including phosphorylation, acetylation/deacetylation, ubiquitination and protein-protein interactions. As FOXO factors play a pivotal role in cell fate decision, mounting evidence suggests that FOXO factors function as tumor suppressors in a variety of cancers. FOXOs are actively involved in promoting apoptosis in a mitochondria-independent and -dependent manner by inducing the expression of death receptor ligands, including Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand, and Bcl-2 family members, such as Bim, bNIP3 and Bcl-X(L), respectively. An understanding of FOXO proteins and their biology will provide new opportunities for developing more effective therapeutic approaches to treat cancer.
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                December 2017
                26 September 2017
                26 September 2017
                : 16
                : 6
                : 8037-8044
                Affiliations
                Shandong Provincial Key Laboratory of Animal Resistant Biology, School of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
                Author notes
                Correspondence to: Professor Guorong Li, Shandong Provincial Key Laboratory of Animal Resistant Biology, School of Life Sciences, Shandong Normal University, 88 East Wenhua Road, Jinan, Shandong 250014, P.R. China, E-mail: grli@ 123456sdnu.edu.cn
                Article
                mmr-16-06-8037
                10.3892/mmr.2017.7612
                5779887
                28983625
                Copyright: © Chai et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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                resveratrol, sirt1, pi3k/akt, dlc1

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