Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression.
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.
Park
Jung Hyun
JH
Department of Rehabilitation Medicine, Eulji University Hospital, Daejeon 302-799, Korea.
Jeong
Yun-Jeong
YJ
Park
Kwan-Kyu
KK
Cho
Hyun-Ji
HJ
Chung
Il-Kyung
IK
Min
Kwan-Sik
KS
Kim
Mihyun
M
Lee
Kwang-Gill
KG
Yeo
Joo-Hong
JH
Park
Kwang-Kyun
KK
Chang
Young-Chae
YC
D001030:Apamin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008555:Melitten / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D008555:Melitten; D001030:Apamin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate