Melittin, a Major Component of Bee Venom, Sensitizes Human Hepatocellular Carcinoma Cells to TRAIL-Induced Apoptosis By Activating CaMKII-TAK1-JNK/p38 and Inhibiting IKK-NFBJ. Biol. Chem, December 12, 2008
Promoting apoptosis is a strategy for cancer drug discovery. Tumor necrosis factor (TNF)-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 aa 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 (CaM)-dependent protein kinase (CaMK), transforming growth factor-ß (TGF-ß)-activated kinase 1 (TAK1) and c-Jun N-terminal kinase (JNK)/p38 MAPK (mitogen-activated protein kinase). We show that melittin-induced apoptosis can be inhibited by calcium chelator, inhibitors for CaMK, JNK and p38, and 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 IBa kinase (IKK)-NFB.
Our data suggest that melittin can synergize with TRAIL in the induction of HCC cell apoptosis by activating CaMK-TAK1-JNK/p38 pathway but inhibiting IKK-NFB pathway.
Therefore, the combination of melittin with TRAIL may be a promising therapeutic approach in the treatment of TRAIL-resistant human cancer.
No comments:
Post a Comment