3-Caffeoyl, 4-dihydrocaffeoylquinic acid from Salicornia herbacea inhibits tumor cell invasion by regulating protein kinase C-delta-dependent matrix metalloproteinase-9 expression.
In this study, we determined the effects of a novel chlorogenic acid, 3-caffeoyl, 4-dicaffeoylquinic acid (CDCQ) isolated from Salicornia herbacea, on tumor invasion and migration in human fibrosarcoma HT-1080 cells and investigated the possible mechanism(s) involved. CDCQ reduced the phorbol myristate acetate (PMA)-induced activation of matrix metalloproteinase (MMP)-9 and MMP-2 and inhibited cell invasion and migration. CDCQ suppressed PMA-induced expression of MMP-9 mRNA and protein by suppressing the transcription factor AP-1, without changing the level of tissue inhibitor of metalloproteinase (TIMP)-1. CDCQ-inhibited PMA-induced MMP-2 expression by suppressing membrane-type 1 MMP (MT1-MMP), but did not alter the TIMP-2 level. CDCQ also inhibited the PMA-induced nuclear translocation of c-Jun and c-Fos, which are upstream of PMA-induced MMP-9 expression. Furthermore, CDCQ strongly repressed PMA-induced phosphorylation of ERK, p38 MAPK, and JNK, which are dependent on the PKCdelta pathway. In conclusion, we demonstrated that the anti-invasive effects of CDCQ occur through the inhibition of AP-1 and signaling pathways involving PKCdelta and three MAPKs, leading to the downregulation of MMP-9 expression. Thus, CDCQ is an effective anti-metastatic agent that functions by downregulating MMP-9 gene expression.
Hwang
Yong Pil
YP
Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea; College of Pharmacy, Chonnam National University, Gwangju, South Korea.
Yun
Hyo Jeong
HJ
Choi
Jae Ho
JH
Chun
Hyo Kon
HK
Chung
Young Chul
YC
Kim
Sang Kyum
SK
Kim
Bong-Hee
BH
Kwon
Kwang-Il
KI
Jeong
Tae Cheon
TC
Lee
Kwang Youl
KY
Jeong
Hye Gwang
HG
D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019663:Chenopodiaceae / Q000737:chemistry*; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C544671:3-caffeoyl-4-dihydrocaffeoylquinic acid; D000972:Antineoplastic Agents, Phytogenic; D002726:Chlorogenic Acid; D051745:Protein Kinase C-delta; D020780:Matrix Metalloproteinase 9