Carcinogenesis Advance Access originally published online on November 26, 2008
Carcinogenesis 2009 30(2):300-307; doi:10.1093/carcin/bgn269
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A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-
B-signaling pathways
Department of Dermatology, School of Medicine and Public Health
1 Division of Pharmacy Practice, School of Pharmacy, University of Wisconsin, Madison, WI 53706, USA
* To whom correspondence should be addressed. Department of Dermatology, Medical Sciences Center, University of Wisconsin, Room #B25, 1300 University Avenue, Madison, WI 53706, USA. Tel: +1 608 263 3927; Fax: +1 608 263 5223; Email: hmukhtar{at}wisc.edu
Overexpression of cyclooxygenase 2 (COX2) and uncontrolled wingless and Int (Wnt)-signaling pathway have long been suggested to play crucial roles in colorectal cancer. Studies show that selective COX2 inhibitors possess great potential as chemopreventive agents for colon cancer. Recent studies suggest that targeting COX2 and epidermal growth factor receptor (EGFR) may provide better therapeutic strategy than inhibiting either single target and that this may alleviate the problem of COX2 inhibitor-associated side effects. Therefore, there have been intensive efforts to develop novel dietary substances that target COX2 and EGFR activation. Fisetin is a naturally occurring flavonoid commonly found in various vegetables and fruits. We found that the treatment of COX2-overexpressing HT29 human colon cancer cells with fisetin (30–120 µM) resulted in induction of apoptosis, downregulation of COX2 protein expression without affecting COX1 and inhibited the secretion of prostaglandin E2. Treatment of cells with fisetin also inhibited Wnt-signaling activity through downregulation of β-catenin and T cell factor 4 and decreased the expression of target genes such as cyclin D1 and matrix metalloproteinase 7. Fisetin treatment of cells also inhibited the activation of EGFR and nuclear factor-kappa B (NF-
B). Finally, the formation of colonies in soft agar was suppressed by fisetin treatment. Taken together, we provide evidence that the plant flavonoid fisetin can induce apoptosis and suppress the growth of colon cancer cells by inhibition of COX2- and Wnt/EGFR/NF-B-signaling pathways. We suggest that fisetin could be a useful agent for prevention and treatment of colon cancer.
Abbreviations: COX, cyclooxygenase; EGFR, epidermal growth factor receptor; EP, E-prostanoid; MMP7, matrix metalloproteinase 7; MT, mutant; NF-B, nuclear factor-kappa B; PG, prostaglandin; TCF, T cell factor; Wnt, wingless and Int; WT, wild-type
Received August 12, 2008; revised October 27, 2008; accepted November 14, 2008.