Curcumin Inhibits Phorbol Ester-Induced Up-Regulation of Cyclooxygenase-2 and Matrix Metalloproteinase-9 by Blocking ERK1/2 Phosphorylation and NF-κB Transcriptional Activity in MCF10A Human Breast Epithelial Cells

Abstract

Elevated levels of cyclooxygenase-2 (COX-2) and matrix metalloproteinases (MMPs) are often observed in various types of cancerous and transformed cells, and hence recognized as potential molecular targets for the chemoprevention. In the present study, we investigated the possible inhibitory effects of curcumin on the expression of COX-2 and MMP-9 induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) in MCF10A human breast epithelial (MCF10A) cells and the underlying mechanisms. Curcumin inhibited the TPA-induced COX-2 expression at both transcriptional and post-transcriptional levels, and reduced the synthesis of prostaglandin E(2), one of the major products of COX-2. Likewise, curcumin attenuated invasiveness and motility of MCF10A cells stimulated with TPA through suppression of MMP expression. Curcumin blocked TPA-induced activation of extracellular signal-regulated protein kinase (ERK1/2) and nuclear factor kappaB (NF-kappaB) transcriptional activity. Overexpression of the dominant negative forms of ERK2 abrogated the TPA-induced NF-kappaB transcriptional activity. Treatment of MCF10A cells with U0126, which is a pharmacological inhibitor of ERK1/2, reduced TPA-induced up-regulation of COX-2 and MMP-9. Taken together, these findings suggest that curcumin inhibits the TPA-induced up-regulation of COX-2 and MMP-9 by suppressing ERK1/2 phosphorylation and NF-kappaB trans-activation in human breast epithelial cells, which may contribute to its chemopreventive potential.

H‐Ras selectively up‐regulates MMP‐9 and COX‐2 through activation of ERK1/2 and NF‐κB: An implication for invasive phenotype in rat liver epithelial cells

“…The H-Ras WB cells were developed from the transfection of WB cells with a retroviral vector containing the v-Ha-ras oncogene and a neomycin-resistant marker. 19 Cells (at passages [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] were cultured in modified Eagle's medium supplemented with 5% fetal bovine serum and penicillin/streptomycin at 37°C in a humidified atmosphere of 5% CO 2 and 95% air.…”

“…We examined the activation of transcription factors NF-jB and AP-1, which have been shown to regulate the expressions of MMP-9 and COX-2, [13][14][15] by performing an EMSA using nuclear extracts of WB and H-Ras WB cells. The DNA binding activity of NF-jB was markedly increased in H-Ras WB cells compared to WB cells (Fig.…”

“…12 The promoter region of the MMP-9 and COX-2 genes has been shown to contain consensus motifs for eukaryotic transcription factors, nuclear factor (NF)-jB and activator protein (AP)-1. [13][14][15] Inappropriate up-regulation of MMPs and COX-2 has been implicated in the pathogenesis of liver cancer. 16,17 The underlying mechanisms, however, have not been defined yet.…”

Anticancer Properties of Curcumin

“…A recent study by our group has shown that curcumin is able to sensitize lung cancer cells to undergo anoikis through a mechanism that involves post-translational modification of Bcl-2 via the ubiquitin-proteasome pathway (Pongrakhananon et al, 2010). Curcumin also acts as a negative regulator of cancer cell migration and invasion through diverse signaling pathways including MMP-9, MMP-2 and COX-2 (Philip et al, 2004, Lee et al, 2005Hong et al, 2006;Lin et al, 2009). Animal and clinical studies of curcumin have been well investigated.…”

The Treatment of Breast Cancer Tumor Growth and Metastasis With an Anti-MMP9 DNAzyme

“…The treatment of DU145 prostate cancer cells with curcumin, an anti-metastatic derivative from tumeric, has been shown to decrease the levels of MMP-2 and -9 and lead to a decrease in tumor volume [79]. Curcumin treatment has also been shown to alter the invasive and metastatic properties of MCF10A human breast epithelial cells [80] and decrease metastasis to lung in a human breast cancer xenograft model [81] by decreasing the levels of MMP-9 and COX-2. According to Eiseler, et al, highly invasive breast cancer human tissue samples, regardless of stage and progesterone or estrogen dependence, were shown to have reduced Protein Kinase D1 (PKD1) expression in greater than 95% of the tumor samples compared to normal breast tissue [82].…”