CADPE Inhibits PMA-Stimulated Gastric Carcinoma Cell Invasion and Matrix Metalloproteinase-9 Expression by FAK/MEK/ERK–Mediated AP-1 Activation

Abstract

Metastasis is one of the main causes of death for patients with malignant tumors. Aberrant expression of matrix metalloproteinase-9 (MMP-9) has been implicated in the invasion and metastasis of various cancer cells. Here, we found that caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) could inhibit the migration and invasion of human gastric carcinoma cells in Transwell migration assays. To understand the underlying mechanism, we showed that CADPE significantly inhibited phorbol 12-myristate 13-acetate (PMA)-induced increases in MMP-9 expression and activity in a dose-dependent manner. The inhibitory effect of CADPE on MMP-9 expression correlated well with the suppression of MMP-9 promoter activity and the reduction of MMP-9 mRNA. Reporter gene assay and electrophoretic mobility shift assay showed that CADPE inhibited MMP-9 expression by suppressing the activation of the nuclear transcription factor activator protein-1 (AP-1) and c-Fos, but not NF-κB. Moreover, CADPE inhibited PMA-induced phosphorylation of protein kinases involved in AP-1 activation, such as focal adhesion kinase (FAK), mitogen-activated protein kinase/ extracellular signal-regulated kinase (ERK) kinase (MEK), and ERK1/2, whereas CADPE had little effect on the phosphorylation of p38 and c-jun NH 2 -terminal kinase. Taken together, our findings indicate that CADPE could be a unique antitumor agent that specifically inhibits MMP-9 activity by targeting the activation of FAK/ MEK/ERK protein kinases and AP-1 transcription factor.

Human Leucine Zipper Protein sLZIP Induces Migration and Invasion of Cervical Cancer Cells via Expression of Matrix Metalloproteinase-9

“…Therefore, regulation of MMP-9 expression in cancer development has been of interest. Although the exact regulatory mechanism of MMP-9 expression in cancer is not clear, MMP-9 expression can be induced by various stimuli, including endothelial growth factor, IL-1␣, TNF-␣, LPS, and 12-O-tetradecanoylphorbol-13-acetate (7,39,40). The promoter region of the human MMP-9 gene contains multiple functional cis-regulatory regions, including binding sites for CREB, AP-1, NF-B, Sp-1, and Ets-1 within the minimal 670-bp MMP-9 promoter, and these sites are critical for the transcriptional activation of MMP-9 that is involved in basal and induced transcriptional responses (11,35,38,41).…”

Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways

“…(21) Caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE), a compound originally isolated from medicinal plants Sarcandra glabra and Teucrium pilosum, (22) has attracted much interest due to its proven pharmacologic safety and its many biologic activities, such as induction of cancer senescence, (23) inhibition of tumor angiogenesis, (24) suppression of hepatocellular carcinoma growth, (25) and gastric carcinoma cell migration. (26) In the present study, we investigated the effects of CADPE on osteoclastogenesis both in vitro and in vivo, and elucidated the underlying molecular mechanisms. We found that CADPE suppressed RANKL-induced osteoclast differentiation within non-growth inhibitory concentrations at an early stage of osteoclastogenesis.…”

Cudratricusxanthone A inhibits endothelial protein C receptor shedding in vitro and in vivo

“…Effects of CTXA on PMA-stimulated phosphorylation of p38MAPK, ERK1/2, and JNK Previous studies have reported involvement of p38MAPK, ERK1/2, and JNK in cytokine-induced EPCR shedding, and increased phosphorylation of p38MAPK, ERK1/2, and JNK was known to occur by stimulation with PMA (Leng et al 2004;Menschikowski et al 2009;Han et al 2010). Therefore, in order to determine the molecular mechanisms of suppression of PMA-induced EPCR shedding by CTXA, the effects of CTXA on PMA-stimulated phosphorylation of p38MAPK, ERK1/2, and JNK were tested.…”

“…Increased phosphorylation of p38MAPK, ERK1/2, and JNK is known to occur by stimulation with PMA (Leng et al 2004;Menschikowski et al 2009;Han et al 2010), and activation of TACE occurs upon activation of ERK or p38 MAPK (Huovila et al 2005;Murphy 2008); therefore, in order to define the processes responsible for inhibition of PMA-stimulated shedding of EPCR and expression of TACE by CTXA, we investigated involvement of MAPK signaling pathways in PMA-stimulated condition. MAPKs comprise a family of highly conserved serine/threonine protein kinases, which are believed to have key roles in mediation of inflammation (Thalhamer et al 2008).…”

“…In vitro studies have reported a dramatic increase in EPCR shedding from the endothelium by a wide variety of inflammatory mediators (IL-1β, H 2 O 2 , and phorbol myristate acetate) and thrombin, and EPCR shedding is potentiated by the microtubule disrupting agent, nocodazole (Xu et al 2000). In addition, phosphorylation of p38MAPK, ERK1/2, and JNK was increased by stimulation with PMA (Leng et al 2004;Menschikowski et al 2009;Han et al 2010), and activation of TACE occurs upon activation of ERK or p38 (Huovila et al 2005;Murphy 2008). …”