Sulindac suppresses β-catenin expression in human cancer cells☆
Introduction
Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), is known to prevent recurrence and reduce colorectal polyps in number and size in patients with familial adenomatous polyposi (Clevers, 2006, Kelloff et al., 2006, Szabo, 2006). The molecular mechanisms underlying these biological effects are not completely understood. Inhibition of cyclooxygenase-2 (COX-2) underlies part of this effect. However, COX-independent mechanisms may also play a role, since NSAIDs inhibit the growth of colon cancer cell lines lacking COX-2 expression (Smith et al., 2000, Zhang et al., 1999). Our previous study showed that cyclin dependent kinase(CDK) inhibitor p21WAF/cip1 was an important determinant of intestinal cell response to sulindac in vitro and in vivo (Yang et al., 2005a, Yang et al., 2001). Our recent study demonstrated that c-jun NH2-terminal kinase 1 (JNK1) was synergistic with p21WAF1 to inhibit cell proliferation and induced apoptosis in vitro and in vivo by sulindac (Song et al., 2007). Other studies have shown that β-catenin could be a target for NSAIDs in colorectal adenomas of patients and colorectal cancer cell lines (Boon et al., 2004, Bordonaro et al., 1999, Dihlmann et al., 2001, Gardner et al., 2004).
The Wnt/β-catenin signaling pathway is tightly regulated and has important functions in development, tissue homeostasis, and regeneration. Oncogenic activation of the Wnt-signalling pathway by mutations in Adenomatous polyposis coli (APC) or β-catenin, which results in the accumulation and nuclear translocation of β-catenin and in β-catenin/T-cell factor (TCF) 4-regulated transcription of TCF target genes such as cyclin D1 and c-myc, is mandatory for the initial neoplastic transformation of intestinal epithelium (Wong and Pignatelli, 2002). Recent studies also found that activation of Wnt/β-catenin signaling is important for both initiation and progression of cancers of different tissues/organs, including liver (Lee et al., 2006), prostate (Terry et al., 2006), breast (Turashvili et al., 2006), esophagus (Clement et al., 2007) and lung (Mazieres et al., 2005). Thus, Wnt/β-catenin signaling is becoming a promising target for chemoprevention and chemotherapy (Herbst and Kolligs, 2007, Luo et al., 2007).
In the present study, we determined the effects of sulindac on breast and lung cancer cells as well as colorectal cancer cells. Our results demonstrated that sulindac inhibited human cancer cell proliferation in breast, lung and colon cancer cells, which was associated with suppression of β-catenin expression and decrease of transcriptional activities and its transcriptional targets cyclin D1, c-myc and cdk4, and that sulindac-induced apoptosis in cancer cells was mainly associated with induction of p21WAF1/cip1.
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Cell lines and cell culture
Colon cancer cell line SW620, breast cancer cell line MCF7 and lung cancer cell line A549 were purchased from the American Type Culture Collection (Manassas, VA). All cells were maintained in MEM medium. The medium was supplemented with 10% (v/v) fetal bovine serum (FBS), 1 × antibiotic/antimycotic (100 units/ml streptomycin, 100 units/ml penicillin, and 0.25 μg/ml amphotericin B). All cell lines were cultured in humidified incubator at 37 °C with 5% CO2. Sulindac (Sigma, St. Louis, MO) was
Sulindac inhibited proliferation of colorectal, breast and lung cancer cells
We and others have reported that sulindac is an effective chemopreventive agent in the prevention of colorectal cancer in vivo and in vitro (Boolbol et al., 1996, Lipkin, 1997, Rao et al., 1995, Reddy et al., 1999, Song et al., 2007, Yang et al., 2005b, Yang et al., 2001). In this study, sulindac was used to elucidate its anticancer ability to breast cancer cell line MCF7 and lung cancer cell line A549, as well as colon cancer cell line SW620. Sulindac was added to the media at a final
Discussion
Our data provides a direct evidence that sulindac inhibits cell proliferation (rather than induces apoptosis) in breast and lung cancer cells, as well as colorectal cancer cells, which is associated with the suppression of β-catenin; and that sulindac induces apoptosis in colon and lung cancer cells, which is associated with the reduction of β-catenin and the induction of p21WAF/cip1. Thus, in addition to colorectal cancer, the Wnt/β-catenin signaling might be a target of sulindac in lung
Acknowledgement
We would like to thank Drs. Barbara Heerdt and Tianhong Li (Albert Einstein Cancer Center, Bronx, NY) and Drs. Jonna Frasor and Zuoming Sun (University of Illinois at Chicago, Chicago, IL) for providing reagents.
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Grants support: This work was supported in part by the National Cancer Institute grant R01CA112081 (to W. Yang) and the American Institute for Cancer Research grant 05A121 (to W. Yang).
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Current address: Department of Pathology, the First Affiliated Hospital and Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.