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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Hepatocellular Carcinoma | Primary research

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

Authors: Guoyan Tian, Jin Chen, Yan Luo, Jin Yang, Tao Gao, Junping Shi

Published in: Cancer Cell International | Issue 1/2019

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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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Literature
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.CrossRef
2.
Fujiyama S, Shibata J, Maeda S, Tanaka M, Noumaru S, Sato K, Tomita K. Phase I clinical study of a novel lipophilic platinum complex (SM-11355) in patients with hepatocellular carcinoma refractory to cisplatin/lipiodol. Br J Cancer. 2003;89(9):1614–9.CrossRef
3.
Okusaka T, Okada S, Nakanishi T, Fujiyama S, Kubo Y. Phase II trial of intra-arterial chemotherapy using a novel lipophilic platinum derivative (SM-11355) in patients with hepatocellular carcinoma. Invest New Drugs. 2004;22(2):169–76.CrossRef
4.
Tian H, Ge C, Zhao F, Zhu M, Zhang L, Huo Q, Li H, Chen T, Xie H, Cui Y, et al. Downregulation of AZGP1 by Ikaros and histone deacetylase promotes tumor progression through the PTEN/Akt and CD44s pathways in hepatocellular carcinoma. Carcinogenesis. 2017;38(2):207–17.PubMed
5.
Yu M, Mu Y, Qi Y, Qin S, Qiu Y, Cui R, Zhong M. Odontogenic ameloblast-associated protein (ODAM) inhibits human colorectal cancer growth by promoting PTEN elevation and inactivating PI3K/AKT signaling. Biomed Pharmacother. 2016;84:601–7.CrossRef
6.
Xiao J, Yu W, Hu K, Li M, Chen J, Li Z. miR-92a promotes tumor growth of osteosarcoma by targeting PTEN/AKT signaling pathway. Oncol Rep. 2017;37(4):2513–21.CrossRef
7.
Zhang X, Chen Y, Zhao P, Zang L, Zhang Z, Wang X. MicroRNA-19a functions as an oncogene by regulating PTEN/AKT/pAKT pathway in myeloma. Leukemia Lymphoma. 2017;58(4):932–40.CrossRef
8.
9.
Tang S, Li Y, Bao Y, Dai Z, Niu T, Wang K, He H, Song D. Novel cytisine derivatives exert anti-liver fibrosis effect via PI3K/Akt/Smad pathway. Bioorg Chem. 2019;90:103032.CrossRef
10.
Getahun A, Wemlinger SM, Rudra P, Santiago ML, van Dyk LF, Cambier JC. Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3 K pathway. J Exp Med. 2017;214(4):931–41.CrossRef
11.
Sun L, Yu F, Yi F, Xu L, Jiang B, Le L, Xiao P. Acteoside from Ligustrum robustum (Roxb.) blume ameliorates lipid metabolism and synthesis in a HepG2 cell model of lipid accumulation. Front Pharmacol. 2019;10:602.CrossRef
12.
Qiu ZC, Zhao XX, Wu QC, Fu JW, Dai Y, Wong MS, Yao XS. New secoiridoids from the fruits of Ligustrum lucidum. J Asian Nat Prod Res. 2018;20(5):431–8.CrossRef
13.
Wang C, Gao H, Cai E, Zhang L, Zheng X, Zhang S, Sun N, Zhao Y. Protective effects of Acanthopanax senticosus–Ligustrum lucidum combination on bone marrow suppression induced by chemotherapy in mice. Biomed Pharmacother. 2019;109:2062–9.CrossRef
14.
Zhang L, Ravipati AS, Koyyalamudi SR, Jeong SC, Reddy N, Bartlett J, Smith PT, de la Cruz M, Monteiro MC, Melguizo A, et al. Anti-fungal and anti-bacterial activities of ethanol extracts of selected traditional Chinese medicinal herbs. Asian Pac J Trop Med. 2013;6(9):673–81.CrossRef
15.
Wu J, Ke X, Fu W, Gao X, Zhang H, Wang W, Ma N, Zhao M, Hao X, Zhang Z. Inhibition of hypoxia-induced retinal angiogenesis by specnuezhenide, an effective constituent of Ligustrum lucidum Ait., through suppression of the HIF-1alpha/VEGF signaling pathway. Molecules. 2016;21(12):1756.CrossRef
16.
Hu B, Du Q, Deng S, An HM, Pan CF, Shen KP, Xu L, Wei MM, Wang SS. Ligustrum lucidum Ait. fruit extract induces apoptosis and cell senescence in human hepatocellular carcinoma cells through upregulation of p21. Oncol Rep. 2014;32(3):1037–42.CrossRef
17.
Barone I, Cui Y, Herynk MH, Coronarodriguez A, Giordano C, Selever J, Beyer A, Andò S, Fuqua SA. Expression of the K303R estrogen receptor α breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway. Can Res. 2009;69(11):4724–32.CrossRef
18.
Vara JÁ, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.CrossRef
19.
Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci USA. 2008;105(24):8292–7.CrossRef
20.
Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, Acevedo LM, Manglicmot JR, Song X, Wrasidlo W, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19(6):715–27.CrossRef
21.
Padala RR, Karnawat R, Viswanathan SB, Thakkar AV, Das AB. Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/beta-catenin signaling network constitutively activate inter-pathway positive feedback loops. Mol BioSyst. 2017;13(5):830–40.CrossRef
22.
Xuan W, Feng X, Qian C, Peng L, Shi Y, Xu L, Wang F, Tan W. Osteoclast differentiation gene expression profiling reveals chemokine CCL4 mediates RANKL-induced osteoclast migration and invasion via PI3K pathway. Cell Biochem Funct. 2017;35(3):171–7.CrossRef
23.
Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.CrossRef
24.
Huang Y, Tan H, Cao Q, Yuan G, Su G, Yang P. Different methylation of CpG-SNPs in Behcet’s disease. Biomed Res Int. 2019;2019:3489305.PubMedPubMedCentral
25.
Traube FR, Carell T. The chemistries and consequences of DNA and RNA methylation and demethylation. RNA Biol. 2017;14(9):1099–107.CrossRef
26.
Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21.CrossRef
27.
Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem. 2005;74:481–514.CrossRef
28.
Straussman R, Nejman D, Roberts D, Steinfeld I, Blum B, Benvenisty N, Simon I, Yakhini Z, Cedar H. Developmental programming of CpG island methylation profiles in the human genome. Nat Struct Mol Biol. 2009;16(5):564–71.CrossRef
29.
Lubecka-Pietruszewska K, Kaufman-Szymczyk A, Stefanska B, Fabianowska-Majewska K. Folic acid enforces DNA methylation-mediated transcriptional silencing of PTEN, APC and RARbeta2 tumour suppressor genes in breast cancer. Biochem Biophys Res Commun. 2013;430(2):623–8.CrossRef
30.
Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA, Hafen E. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science. 2002;295(5562):2088–91.CrossRef
31.
Wu X, Hepner K, Castelino-Prabhu S, Do D, Kaye MB, Yuan XJ, Wood J, Ross C, Sawyers CL, Whang YE. Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc Natl Acad Sci USA. 2000;97(8):4233–8.CrossRef
32.
Schneider E, Keppler R, Prawitt D, Steinwender C, Roos FC, Thuroff JW, Lausch E, Brenner W. Migration of renal tumor cells depends on dephosphorylation of Shc by PTEN. Int J Oncol. 2011;38(3):823–31.PubMed
33.
Goo CK, Lim HY, Ho QS, Too HP, Clement MV, Wong KP. PTEN/Akt signaling controls mitochondrial respiratory capacity through 4E-BP1. PLoS ONE. 2012;7(9):e45806.CrossRef
34.
Hua S, Yao M, Vignarajan S, Witting P, Hejazi L, Gong Z, Teng Y, Niknami M, Assinder S, Richardson D, et al. Cytosolic phospholipase A2alpha sustains pAKT, pERK and AR levels in PTEN-null/mutated prostate cancer cells. Biochem Biophys Acta. 2013;1831(6):1146–57.PubMed
35.
Bai ZG, Ye YJ, Shen DH, Lu YY, Zhang ZT, Wang S. PTEN expression and suppression of proliferation are associated with Cdx2 overexpression in gastric cancer cells. Int J Oncol. 2013;42(5):1682–91.CrossRef
Metadata
Title
Ethanol extract of Ligustrum lucidum Ait. leaves suppressed hepatocellular carcinoma in vitro and in vivo
Authors
Guoyan Tian
Jin Chen
Yan Luo
Jin Yang
Tao Gao
Junping Shi
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0960-5

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