Article

Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB.

Department of Integrative Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.
Journal of Biological Chemistry (impact factor: 4.77). 01/2009; 284(6):3804-13. DOI:10.1074/jbc.M807191200 pp.3804-13
Source: PubMed

ABSTRACT Promoting apoptosis is a strategy for cancer drug discovery. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of malignant cells. However, several cancers, including human hepatocellular carcinoma (HCC), exhibit a major resistance to TRAIL-induced cell death. Melittin, a water-soluble 26-amino acid peptide derived from bee venom of Apis mellifera, can exert toxic or inhibitory effects on many types of tumor cells. Here we report that melittin can induce apoptosis of HCC cells by activating Ca2+/calmodulin-dependent protein kinase, transforming growth factor-beta-activated kinase 1 (TAK1), and JNK/p38 MAPK. We show that melittin-induced apoptosis can be inhibited by calcium chelator, by inhibitors for Ca2+/calmodulin-dependent protein kinase, JNK and p38, and by dominant negative TAK1. In the presence of melittin, TRAIL-induced apoptosis is significantly increased in TRAIL-resistant HCC cells, which may be attributed to melittin-induced TAK1-JNK/p38 activation and melittin-mediated inhibition of IkappaBalpha kinase-NFkappaB. Our data suggest that melittin can synergize with TRAIL in the induction of HCC cell apoptosis by activating the TAK1-JNK/p38 pathway but inhibiting the IkappaBalpha kinase-NFkappaB pathway. Therefore, the combination of melittin with TRAIL may be a promising therapeutic approach in the treatment of TRAIL-resistant human cancer.

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    Article: Mucroporin-M1 Inhibits Hepatitis B Virus Replication by Activating the Mitogen-activated Protein Kinase (MAPK) Pathway and Down-regulating HNF4 in Vitro and in Vivo *
    Zhenhuan Zhao, Wei Hong, Zhengyang Zeng, Yingliang Wu, Kanghong Hu, Xiaohui Tian, Wenxin Li, Zhijian Cao
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    ABSTRACT: Background: Mucroporin-M1 is a scorpion venom-derived peptide. Results: Mucroporin-M1 peptide activates the MAPK pathway, and then reduces the expression of HNF4, resulting in the inhibition of HBV replication in vitro and in vivo. Conclusion: Mucroporin-M1 inhibits HBV replication by activating MAPK pathway and down-regulating HNF4. Significance: New-resourced peptide inhibits HBV replication by a novel mechanism. Hepatitis B virus (HBV) is a noncytopathic human hepadna-virus that causes acute, chronic hepatitis and hepatocellular car-cinoma (HCC). As the clinical utility of current therapies is lim-ited, new anti-HBV agents and sources for such agents are still highly sought after. Here, we report that Mucroporin-M1, a scorpion venom-derived peptide, reduces the amount of extra-cellular HBsAg, HBeAg, and HBV DNA productions of HepG2.2.15 cells in a dose-dependent manner and inhibits HBV capsid DNA, HBV intracellular RNA replication intermediates and the HBV Core protein in the cytoplasm of HepG2.2.15 cells. Using a mouse model of HBV infection, we found that HBV replication was significantly inhibited by intravenous injection of the Mucroporin-M1 peptide. This inhibitory activity was due to a reduction in HBV promoter activity caused by a decrease in the binding of HNF4 to the precore/core promoter region. Furthermore, we confirmed that Mucroporin-M1 could selec-tively activate mitogen-activated protein kinases (MAPKs) and lead to the down-regulation of HNF4 expression, which explains the decreased binding of HNF4 to the HBV promoter. Moreover, when the protein phosphorylation activity of the MAPK pathway was inhibited, both HNF4 expression and HBV replication recovered. Finally, we proved that treatment with the Mucroporin-M1 peptide increased phosphorylation of the MAPK proteins in HBV-harboring mice. These results implicate Mucroporin-M1 peptide can activate the MAPK path-way and then reduce the expression of HNF4, resulting in the inhibition of HBV replication in vitro and in vivo. Our work also opens new doors to discovering novel anti-HBV agents or sources.
    Journal of Biological Chemistry 07/2012; · 4.77 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

activating Ca2+/calmodulin-dependent protein kinase
 
Ca2+/calmodulin-dependent protein kinase
 
cancer drug discovery
 
dominant negative TAK1
 
growth factor-beta-activated kinase 1
 
HCC cell apoptosis
 
HCC cells
 
human hepatocellular carcinoma
 
IkappaBalpha kinase-NFkappaB pathway
 
major resistance
 
malignant cells
 
melittin-induced apoptosis
 
melittin-induced TAK1-JNK/p38 activation
 
melittin-mediated inhibition
 
promising therapeutic approach
 
TAK1-JNK/p38 pathway
 
TRAIL-induced cell death
 
TRAIL-resistant HCC cells
 
TRAIL-resistant human cancer
 
tumor cells
 

Chen Wang