Carcinogenesis Advance Access published online on November 26, 2008
Carcinogenesis, 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
1 Department of Dermatology, School of Medicine and Public Health
2 Division of Pharmacy Practice, School of Pharmacy, University of Wisconsin, Madison, WI, USA
Send correspondence to: Hasan Mukhtar, Ph.D., Helfaer Professor of Cancer Research, Director and Vice Chair of Research, Department of Dermatology, University of Wisconsin, Medical Sciences Center, Room #B25, 1300 University Avenue, Madison, WI 53706. Phone: (608) 263-3927; Fax: (608) 263-5223, Email: hmukhtar{at}wisc.edu
Overexpression of cyclooxygenase 2 (COX2) and uncontrolled 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 PGE2. Treatment of cells with fisetin also inhibited Wnt signaling activity through downregulation of β-catenin and TCF 4, and decreased the expression of target genes such as cyclin D1 and MMP7. 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.
Key Words: Fisetin • colon cancer • COX2 • Wnt • β-catenin
Received August 12, 2008; revised October 27, 2008; accepted November 14, 2008.