Suppression of PMA-induced tumor cell invasion and metastasis by aqueous extract isolated from Prunella vulgaris via the inhibition of NF-kappaB-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 effects of tumor cell migration and invasion by aqueous extract isolated from Prunella vulgaris (PVAE) using in vitro and in vivo assays. PVAE reduced PMA-induced activation of MMP-9 and further inhibited cell invasion and migration. PVAE suppressed PMA-enhanced expression of MMP-9 protein, mRNA and transcription activity levels through suppression of NF-kappaB activation without changing the tissue inhibitor of metalloproteinase level. PVAE inhibited PMA-induced NF-kappaB nuclear translocation, which is upstream of PMA-induced MMP-9 expression and invasion. Furthermore, pretreatment with NF-kappaB activation inhibitor inhibited the PMA-induced MMP-9 expression and activity. PVAE repressed the PMA-induced phosphorylation of ERK1/2, which is upstream signaling molecules in MMP-9 expression. We confirmed that the inhibitory effect of PVAE on lung metastasis and tumor cell growth using B16-F10 melanoma cells or B16-F1 melanoma cells in C57BL/6 mice. The oral administrations of PVAE reduced the lung metastasis and tumor cell growth by B16-F10 or B16-F1 melanoma cells. These results suggested that the anti-metastatic effect of PVAE is mediated through the suppression of MMP-9 expression by the inhibition of NF-kappaB via ERK1/2 signaling pathway as well as MMP-9 activity.
Choi
Jae Ho
JH
College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
Han
Eun Hee
EH
Hwang
Yong Pil
YP
Choi
Jun Min
JM
Choi
Chul Yung
CY
Chung
Young Chul
YC
Seo
Jong Kwon
JK
Jeong
Hye Gwang
HG
D000284:Administration, Oral; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D031347:Prunella / Q000737:chemistry*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014178:Translocation, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D016328:NF-kappa B; D010936:Plant Extracts; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate