Sulindac Inhibits β-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients

Koornstra, Jan J.; Rijcken, Fleur E.M.; Oldenhuis, Corina N.A.M.; Zwart, Nynke; Sluis, Tineke van der; Hollema, Harry; deVries, E. G. E.; Keller, Josbert J.; Offerhaus, Johan; Giardiello, Francis M.; Kleibeuker, Jan H.

doi:10.1158/1055-9965.epi-05-0112

Cited by 30 publications

(15 citation statements)

References 32 publications

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“…In H292EMP cells, typically a threefold activation of TOPFLASH reporter was observed (Figure 3d). Boon et al, 2004;Koornstra et al, 2005). Sulindac sulfone belongs to the family of nonsteroidal anti-inflammatory drugs and has been shown in vitro and in vivo to induce b-catenin degradation through proteosome-and caspase-dependent mechanisms (Klaus and Birchmeier, 2008).…”

Section: Emmprin Regulates B-catenin Signalingmentioning

confidence: 99%

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

et al. 2010

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Advances in the field of tumor biology have identified that tumor cells co-opt developmental signaling pathways of embryonic stem cells and thus gain the ability to proliferate, differentiate and alter cell-cell interactions. One such pathway is the Wnt/b-catenin signaling pathway. High levels of EMMPRIN expression have been shown to correlate with poor prognosis and metastasis in a broad range of tumors. Although a variety of functions are attributed to EMMPRIN in tumorigenesis, the specific mechanism(s) through which it can exert its effects have not been elucidated, until now. In this study, we identify EMMPRIN as a novel regulator of the canonical Wnt/ b-catenin signaling pathway in lung cancer. Increasing EMMPRIN expression levels in lung cancer epithelial cells upregulated the b-catenin signaling pathway and silencing EMMPRIN inhibited b-catenin signaling, cell migration, proliferation, anchorage-independent growth and tumor growth in a mouse tumor xenograft model. These results provide a compelling rationale for targeting EMMPRIN for anticancer therapies. Understanding the molecular mechanisms driving EMMPRIN-induced lung tumorigenesis will provide enormous benefits in developing new therapeutic treatments for this and other forms of cancer.

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Section: Emmprin Regulates B-catenin Signalingmentioning

confidence: 99%

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

et al. 2010

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“…NSAIDs, including celecoxib, sulindac and aspirin, can increase the phosphorylation of β-catenin, thus decreasing its nuclear accumulation and transcription of Wnt/β-catenin target genes, such as cyclin D1, c-myc , and PPAR δ (17–22). Sulindac has also been shown to inhibit β-catenin expression in FAP-related adenomas (21, 23). …”

Section: Introductionmentioning

confidence: 99%

Ibuprofen Inhibits Activation of Nuclear β-Catenin in Human Colon Adenomas and Induces the Phosphorylation of GSK-3β

Greenspan

Madigan

Boardman

et al. 2011

Cancer Prevention Research

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Nonselective cyclooxygenase (COX) inhibitors target many of the same cancer-associated molecular pathways as COX-2-specific inhibitors. Although these nonsteroidal anti-inflammatory drugs (NSAIDs) are often associated with gastrointestinal toxicity, there is renewed interest in their use as colorectal cancer (CRC) chemopreventive agents due to the adverse side effects associated with long-term use of selective COX-2 inhibitors. In this study, we investigated the effects of long-term use (up to 25 years) of NSAIDs (ibuprofen or aspirin) on adenoma pathology and b-catenin-mediated signaling in sporadic human colon adenomas. Although NSAID use did not impact overall adenoma size or degree of dysplasia, it did cause a significant inhibition of nuclear b-catenin localization, which correlated with suppression of cyclin D1 expression. To further elucidate the effect of these agents in regulating b-catenin, we treated SW480 colon cancer cells with a panel of NSAIDs and determined their effects on b-catenin levels and cellular localization. In agreement with our in vivo results, both S-ibuprofen and aspirin were found to decrease total levels of b-catenin while increasing its phosphorylation. In addition, S-ibuprofen induced both degradation of IkBa and nuclear localization of NF-kB. Despite its nuclear localization, however, the activation of the NF-kB target genes, Bcl-2, survivin, and cyclin D1, was suppressed. This reduction in NF-kB transcriptional activity may be due to increased phosphorylation of GSK-3b following S-ibuprofen treatment. These data suggest that ibuprofen can effectively target both the Wnt/b-catenin and NF-kB pathways, and potentially uncovers a novel mechanism through which NSAIDS may exert their chemopreventive efficacy.

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“…The growing evidence has indicated that sulindac targets nuclear β-catenin accumulation and Wnt signaling in colorectal cancers in vivo and in vitro (Boon et al, 2004;Chang et al, 2005;Gardner et al, 2004;He et al, 1999;Koornstra et al, 2005;Rice et al, 2003;Rice et al, 2006), but that sulindac targeting β-catenin in other sites is rare. Even recent report indicated that NSAIDs inhibition of β-catenin required the high level expression of peroxisome proliferators-activated receptor γ (PPAR-γ) and its co-receptor retinoid-X-receptor α (RXR-α) (Lu et al, 2005), how they are interacting to the response to NSAIDs remains unclear and needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Sulindac suppresses β-catenin expression in human cancer cells

Han

Song

Tong

et al. 2008

European Journal of Pharmacology

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Sulindac has been reported to be effective in suppressing tumor growth through the induction of p21WAF1/cip1 in human, animal models of colon cancer and colon cancer cells. In this study, we treated human breast cancer cell line MCF-7 and lung cancer cell line A549 as well as colon cancer cell line SW620 with sulindac to observe the effects of sulindac in other tissue sites. In all cell lines, proliferation was significantly inhibited by sulindac after 24 and 72 h of treatment. Apoptosis was induced by sulindac in both lung cancer cells and colon cancer cells but was not induced in breast cancer cells. Western blots showed that p21 protein level were induced by sulindac in lung cancer cells and colon cancer cells, but not in breast cancer cells. Most importantly, the suppression of β-catenin, a key mediator of Wnt signaling pathway, was seen in all three cell lines with sulindac administration. Further studies revealed that transcriptional activities of β-catenin were significantly inhibited by sulindac and that the inhibition was sulindac dosage-dependent. The transcriptional targets of β-catenin, c-myc, cyclin D1 and cdk 4 were also dramatically downregulated. In conclusion, our data demonstrated that the efficacy of sulindac in the inhibition of cell proliferation (rather than the induction of apoptosis) might be through the suppression of β-catenin pathway in human cancer cells.

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Sulindac Inhibits β-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients

Cited by 30 publications

References 32 publications

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

Ibuprofen Inhibits Activation of Nuclear β-Catenin in Human Colon Adenomas and Induces the Phosphorylation of GSK-3β

Sulindac suppresses β-catenin expression in human cancer cells

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