Abstract
BackgroundThe present study investigated the pharmacological activity and mechanism of ethanol extract of Ligustrum lucidum Ait. leaves (EEL) on HCC.MethodsCell 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.ResultsEEL 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.ConclusionsEEL 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.
Highlights
The present study investigated the pharmacological activity and mechanism of ethanol extract of Ligustrum lucidum Ait. leaves (EEL) on Hepatocellular carcinoma (HCC)
Previous researches showed that the Phosphoinositide 3-kinase (PI3K)/ PTEN/Akt pathway was closely involved in malignant tumors such as hepatocellular carcinoma, hematological neoplasms and lymphoma [4,5,6,7]
EEL decreased the cell viability of Bel‐7402 and Huh‐7 cell counting kit-8 (CCK-8) assay was carried out to evaluate the cytotoxicity of EEL on HCC cells, the results showed that EEL produced limited cytotoxicity to HCC cells at the concentration of 5 mg/ml
Summary
The present study investigated the pharmacological activity and mechanism of ethanol extract of Ligustrum lucidum Ait. leaves (EEL) on HCC. Hepatocellular carcinoma (HCC) has the second highest mortality rate worldwide [1]. As Molecular target therapy in cancer treatment has attracted much attention and it is necessary to further understand the molecular mechanism of HCC progression. Previous researches showed that the PI3K/ PTEN/Akt pathway was closely involved in malignant tumors such as hepatocellular carcinoma, hematological neoplasms and lymphoma [4,5,6,7]. PIP2, and generates PIP3 which is used by PDK1/ PDPK1 (3-phosphoinositide-dependent protein kinase 1) to phosphorylate AKT. As the first discovered cancer suppressor gene with bispecific phosphatase activity, PTEN has been reported to be able to inhibit the activation of Phosphoinositide 3-kinase (PI3K) and affects the phosphorylation level of its downstream target Akt [10]
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