Melittin Suppresses PMA-Induced Tumor Cell Invasion by Inhibiting NF-κB and AP-1-Dependent MMP-9 Expression

Abstract

Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. In this study, we examined the inhibitory effect of bee venom (BV) and its major peptides, melittin and apamin, on PMA-induced invasion induced by MMP-9 expression in Caki-1 renal cancer cells. BV and melittin, but not apamin, significantly suppressed PMA-induced invasion by inhibiting MMP-9 expression in Caki-1 cells. Furthermore, as evidenced by MMP-9 promoter assays, melittin inhibited MMP-9 gene expression by blocking the PMA-stimulated activations of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB). In addition, melittin suppressed the PMA-induced phosphorylations of ERK and JNK mitogen-activated protein kinases, upstream factors involved in Ap-1 and NF-kappaB. These results suggest that the suppression of MMP-9 expression contributes to the anti-tumor properties of melittin.

Inhibitory effect of Trolox on the migration and invasion of human lung and cervical cancer cells

“…PMA increased expression and the enzymatic activity of MMP-9, whereas MMP-2 expression was not affected by PMA. Although we did not compare the basal expression levels and the activities of either MMP-2 or -9 in A549 and HeLa cells, our results support a previous report that MMP-2 is constitutively overexpressed in metastatic cancer cells (7). We also found that Trolox inhibits PMA-induced expression and the proteolytic activity of MMP-9 in both cancer cells.…”

“…MMP-2 is highly expressed in metastatic cancers (7). MMP-9 is also up-regulated in metastatic cancer cells and is implicated in a wide range of pathologic conditions, including inflammation and tissue repair (5).…”

“…In addition, both are highly expressed in various cancers and are closely related to invasion, metastasis, and the epithelial-mesenchymal transition in cancer cells (5,6). MMP-2 is essentially expressed in metastatic cancers, while MMP-9 is regulated by diverse growth factors, cytokines and xenobiotics, such as phorbol 12-myristate 13-acetate (PMA) (7). Induction of MMP-9 is notably important in the invasive ability of human cancers, including lung and cervical cancers (8,9) and suppression of MMP-9 inhibits invasion of lung and cervical cancer cells (10).…”

Synergistic Effects of Bee Venom and Natural Killer Cells on B16F10 Melanoma Cell Growth Inhibition through IL-4-mediated Apoptosis

“…It has been used in oriental medicine for many years to treat inflammatory diseases 8) , and in Korean medicine in pharmacopuncture to treat back pain, rheumatism, and many skin diseases due to its antibacterial, antiviral, and anti-inflammatory effects 9,10) . BV consists of a complex mixture of proteins, peptides, and low molecular weight components.…”

“…BV increases pro-apoptotic proteins by increasing the expression of death receptor (DR) in the cell surface and simultaneously inhibiting the activity of anti-apoptosis factors [11][12][13][14] . Several experimental studies have demonstrated that BV and/or melittin have anti-cancer effects 9,10,15) . Additionally, it has been reported that BV enhances the cytotoxic effects of NK cells on human lung cancer and acts synergistically with NK cells to inhibit cancer cell growth 16,17) .…”