Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1

Abstract

High expression of epidermal growth factor receptor (EGFR) is found in a variety of solid tumors, including colorectal cancer. EGFR has been identified as a rational target for anticancer therapy. Curcumin, the yellow pigment of turmeric in curry, has received attention as a promising dietary supplement for cancer prevention and treatment. We recently reported that curcumin inhibited the growth of human colon cancer-derived Moser cells by suppressing gene expression of cyclinD1 and EGFR. The aim of the present study was to explore the molecular mechanisms underlying curcumin inhibition of gene expression of EGFR in colon cancer cells. The generality of the inhibitory effect of curcumin on gene expression of EGFR was verified in other human colon cancer-derived cell lines, including Caco-2 and HT-29 cells. Promoter deletion assays and sitedirected mutageneses identified a binding site for the transcription factor early growth response-1 (Egr-1) in egfr promoter as a putative curcumin response element in regulating the promoter activity of the gene in Moser cells. Electrophoretic mobility shift assays demonstrated that curcumin significantly reduced the DNA-binding activity of the transcription factor Egr-1 to the curcumin response element. In addition, curcumin reduced the trans-activation activity of Egr-1 by suppressing egr-1 gene expression, which required interruption of the ERK signal pathway and reduction of the level of phosphorylation of Elk-1 and its activity. Taken together, our results demonstrated that curcumin inhibited human colon cancer cell growth by suppressing gene expression of EGFR through reducing the trans-activation activity of Egr-1. These results provided novel insights into the mechanisms of curcumin inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.

Curcumin enhances the effects of 5‐fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF‐1R

“…25,30 The mechanism of inhibition of these transcription factors is less clear. There is some evidence that curcumin inhibits ligand-induced activation of EGFR and decreases its transcription via inhibition of erg-1 transcription factor, 31 although its effect on other EGFRs and IGF-1R is not well studied. Curcumin has also been shown to be an effective inhibitor of cell growth in prostatglandin-synthesis deficient cancer cells (HCT-15), suggesting that it may also act via prostaglandin independent pathways.…”

Curcumin Reorganizes miRNA Expression in a Mouse Model of Liver Fibrosis

“…Curcumin (CM) presents in Curcuma longa herb as a biphenyl compound, possesses anti-inflammatory, antioxidant, wound healing and antimicrobial activities (Maheshwari et al, 2006) and has chemopreventive potential for several cancers (Perkins et al, 2002;Dorai et al, 2004;Choudhuri et al, 2005;Chen et al, 2006) by blocking steps in the carcinogenesis. CM acts on multiple targets and inhibits activation of key cell signaling mediators including NFκB, AP-1, Cox-2, MMP9 and EGFR (Chen et al, 2006;Shishodia et al, 2007).…”

“…CM acts on multiple targets and inhibits activation of key cell signaling mediators including NFκB, AP-1, Cox-2, MMP9 and EGFR (Chen et al, 2006;Shishodia et al, 2007).…”

Curcumin Inhibition of the Functional Interaction between Integrin α6β4 and the Epidermal Growth Factor Receptor

“…There is accumulating evidence that curcumin inhibits cancer initiation and progression through regulation of multiple cellular pathways including EGFR/PDGFR (plateletderived growth factor receptor; refs. 4,5), AKT/mTOR (6, 7), NF-kB (8), MAPK (9), and STAT pathways (10). Most of these curcumin targets are either signaling partners or downstream effectors of integrin a6b4 (11)(12)(13), and our recent study showed that curcumin indeed inhibits a6b4 signaling and functions associated with cancer cell motility and invasion (14).…”