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蜂毒肽通过下调人肝癌HepG2细胞中的组蛋白去乙酰化酶2（HDAC2）来恢复PTEN表达。

Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells.

作者信息

Zhang Hui, Zhao Bin, Huang Cheng, Meng Xiao-Ming, Bian Er-Bao, Li Jun

机构信息

School of pharmacy, Anhui key laboratory of bioactivity of natural products, Anhui Medical University, Hefei, Anhui Province, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei, Anhui Province, China.

出版信息

PLoS One. 2014 May 2;9(5):e95520. doi: 10.1371/journal.pone.0095520. eCollection 2014.

DOI:10.1371/journal.pone.0095520
PMID:24788349
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4008415/
Abstract

Melittin is a water-soluble toxic peptide derived from the venom of the bee. Although many studies show the anti-tumor activity of melittin in human cancer including glioma cells, the underlying mechanisms remain elusive. Here the effect of melittin on human hepatocelluar carcinoma HepG2 cell proliferation in vitro and further mechanisms was investigated. We found melittin could inhibit cell proliferation in vitro using Flow cytometry and MTT method. Besides, we discovered that melittin significantly downregulated the expressions of CyclinD1 and CDK4. Results of western Blot and Real-time PCR analysis indicated that melittin was capable to upregulate the expression of PTEN and attenuate histone deacetylase 2 (HDAC2) expression. Further studies demonstrated that knockdown of HDAC2 completely mimicked the effects of melittin on PTEN gene expression. Conversely, it was that the potential utility of melittin on PTEN expression was reversed in cells treated with a recombinant pEGFP-C2-HDAC2 plasmid. In addition, treatment with melittin caused a downregulation of Akt phosphorylation, while overexpression of HDAC2 promoted Akt phosphorylation. These findings suggested that the inhibitory of cell growth by melittin might be led by HDAC2-mediated PTEN upregulation, Akt inactivation, and inhibition of the PI3K/Akt signaling pathways.

摘要

蜂毒肽是一种源自蜜蜂毒液的水溶性毒性肽。尽管许多研究表明蜂毒肽在包括胶质瘤细胞在内的人类癌症中具有抗肿瘤活性，但其潜在机制仍不清楚。在此，研究了蜂毒肽对人肝癌HepG2细胞体外增殖的影响及其进一步的机制。我们发现，使用流式细胞术和MTT法，蜂毒肽可在体外抑制细胞增殖。此外，我们发现蜂毒肽显著下调细胞周期蛋白D1（CyclinD1）和细胞周期蛋白依赖性激酶4（CDK4）的表达。蛋白质免疫印迹法（western Blot）和实时定量聚合酶链反应（Real-time PCR）分析结果表明，蜂毒肽能够上调第10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）的表达，并减弱组蛋白去乙酰化酶2（HDAC2）的表达。进一步的研究表明，敲低HDAC2完全模拟了蜂毒肽对PTEN基因表达的影响。相反，在用重组pEGFP-C2-HDAC2质粒处理的细胞中，蜂毒肽对PTEN表达的潜在作用被逆转。此外，用蜂毒肽处理导致Akt磷酸化下调，而HDAC2的过表达促进Akt磷酸化。这些发现表明，蜂毒肽对细胞生长的抑制作用可能是由HDAC2介导的PTEN上调、Akt失活以及对磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/Akt）信号通路的抑制所导致的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57bb/4008415/8ab3a9571ba0/pone.0095520.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57bb/4008415/fd91797157c8/pone.0095520.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57bb/4008415/8ab3a9571ba0/pone.0095520.g009.jpg
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