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      Ethanol extract of Ligustrum lucidum Ait. leaves suppressed hepatocellular carcinoma in vitro and in vivo

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          Abstract

          Background

          The present study investigated the pharmacological activity and mechanism of ethanol extract of Ligustrum lucidum Ait. leaves (EEL) on HCC.

          Methods

          Cell viability was determined using cell counting kit-8 (CCK-8) assay. The effects of EEL on cellular biological activities were analyzed by flow cytometry (FCM), cell wound scratch assay and transwell assay. The expression levels of related mRNA and protein were determined by performing quantitative real-time PCR (qRT-PCR), Western blotting assay and immunocytochemistry. Methylation-specific PCR (MSP) was carried out to investigate the possible mechanism underlying the DNA methylation of PTEN.

          Results

          EEL showed cytotoxicity to both Bel-7402 and Huh-7 cell lines. We also found that EEL enhanced the apoptosis of Bel-7402 and Huh-7 cells by regulating the expressions of Bcl-2 associated X (Bax), B cell lymphoma 2 (Bcl-2) and Cytochrome-C and the activity of caspase-3 and therefore promoted cell cycle arrest. Moreover, EEL also suppressed cell migration and invasion. EEL increased the expression of tissue inhibitor of metalloproteinases 2 (TIMP2) but decreased the expressions of matrix metalloproteinase2 (MMP2) and MMP9. Furthermore, EEL inhibited the phosphorylation of PI3K/Akt pathway. MSP results showed that EEL promoted the demethylation of PTEN, suggesting that the inactivation of PI3K/Akt may be related to DNA de-methylation of PTEN. In addition, EEL inhibited the tumor growth of HCC in vivo.

          Conclusions

          EEL exerted anti-tumor effect on HCC in vitro and in vivo. EEL mediated by the inhibition of PI3K/Akt may be closely related to DNA de-methylation of PTEN. Thus, EEL could be used as a potential anti-cancer therapeutic agent of HCC.

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          Most cited references29

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          Developmental programming of CpG island methylation profiles in the human genome.

          Ravid Straussman, Deborah Nejman, Nissim Benvenisty … (2009)
          CpG island-like sequences are commonly thought to provide the sole signals for designating constitutively unmethylated regions in the genome, thus generating open chromatin domains within a sea of global repression. Using a new database obtained from comprehensive microarray analysis, we show that unmethylated regions (UMRs) seem to be formed during early embryogenesis, not as a result of CpG-ness, but rather through the recognition of specific sequence motifs closely associated with transcription start sites. This same system probably brings about the resetting of pluripotency genes during somatic cell reprogramming. The data also reveal a new class of nonpromoter UMRs that become de novo methylated in a tissue-specific manner during development, and this process may be involved in gene regulation. In short, we show that UMRs are an important aspect of genome structure that have a dynamic role in development.
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            The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma.

            Robin Smith, Faruk Ramadani, Klaus Okkenhaug … (2008)
            The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110alpha, p110beta, and p110delta) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110alpha and p110delta to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110gamma class IB PI3K lack SH2 domains and instead couple p110gamma to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110beta and cells derived from a p110beta-deficient mouse line, that p110beta is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110beta and p110gamma contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110beta but not p110gamma, p110beta mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1-phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110gamma in these cells reduced the contribution of p110beta to GPCR signaling. Taken together, these data show that p110beta and p110gamma can couple redundantly to the same GPCR agonists. p110beta, which shows a much broader tissue distribution than the leukocyte-restricted p110gamma, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110gamma expression is low or absent.
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              Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.

              X. Wu, K Hepner, S Castelino-Prabhu … (2000)
              PTEN is a tumor suppressor gene mutated in human cancers. Although many mutations target the phosphatase domain, others create a truncated protein lacking the C-terminal PDZ-binding motif or a protein that extends beyond the PDZ-binding motif. Using the yeast two-hybrid system, we isolated a membrane-associated guanylate kinase family protein with multiple PDZ domains [AIP-1 (atrophin interacting protein 1), renamed MAGI-2 (membrane associated guanylate kinase inverted-2)]. MAGI-2 contains eight potential protein-protein interaction domains and is localized to tight junctions in the membrane of epithelial cells. PTEN binds to MAGI-2 through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. MAGI-2 enhances the ability of PTEN to suppress Akt activation. Furthermore, certain PTEN mutants have reduced stability, which is restored by adding the minimal PDZ-binding motif back to the truncated protein. We propose that MAGI-2 improves the efficiency of PTEN signaling through assembly of a multiprotein complex at the cell membrane.
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                Author and article information

                Contributors
                Guoyan Tian: guoyantian1gyt@163.com
                Jin Chen: jinchen46c@163.com
                Yan Luo: yanluo27ly@163.com
                Jin Yang: jingyang35yj@163.com
                Tao Gao: taogao79gt@163.com
                Junping Shi:
                ORCID: http://orcid.org/0000-0002-4675-7776
                86-571-88015050 , junpingshi95psj@163.com
                Journal
                Journal ID (nlm-ta): Cancer Cell Int
                Journal ID (iso-abbrev): Cancer Cell Int
                Title: Cancer Cell International
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1475-2867
                Publication date (Electronic): 26 September 2019
                Publication date PMC-release: 26 September 2019
                Publication date Collection: 2019
                Volume: 19
                Electronic Location Identifier: 246
                Affiliations
                [1 ]GRID grid.460074.1, Department of Oncology and Hematology, , The Affiliated Hospital of Hangzhou Normal University, ; Hangzhou, Zhejiang Province China
                [2 ]ISNI 0000 0000 8744 8924, GRID grid.268505.c, The Fourth Clinical Medical College, , Zhejiang Chinese Medicine University, ; Hangzhou, Zhejiang Province China
                [3 ]GRID grid.460074.1, Institute of Translational Medicine, , The Affiliated Hospital of Hangzhou Normal University, ; Hangzhou, Zhejiang Province China
                [4 ]ISNI 0000 0004 1764 518X, GRID grid.469513.c, TCM Gynecology, , Hangzhou Hospital of Traditional Chinese Medicine, ; Hangzhou, Zhejiang Province China
                [5 ]GRID grid.460074.1, Department of Liver Diseases, , The Affiliated Hospital of Hangzhou Normal University, ; Hangzhou, Zhejiang Province China
                Author information
                http://orcid.org/0000-0002-4675-7776
                Article
                Publisher ID: 960
                DOI: 10.1186/s12935-019-0960-5
                PMC ID: 6761729
                SO-VID: 8c35fc10-d7e7-49b1-8bee-b1702f270ffa
                Copyright © © The Author(s) 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 15 May 2019
                Date accepted : 13 September 2019
                Funding
                Funded by: Natural Science Foundation of Zhejiang Province
                Award ID: LY17H030009
                Award ID: LQ17H070002
                Funded by: Health Bureau of Hangzhou
                Award ID: 2015A10
                Funded by: Traditional Chinese Medicine Science and Technology Project of Zhejiang Province
                Award ID: 2018ZA098
                Funded by: Hangzhou Science and Technology Bureau
                Award ID: 20163501Y09
                Award ID: 20170533B42
                Categories
                Subject: Primary Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: ethanol extract of ligustrum lucidum ait. leaves (eel),hepatocellular carcinoma (hcc),dna methylation
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: ethanol extract of ligustrum lucidum ait. leaves (eel), hepatocellular carcinoma (hcc), dna methylation

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