Cyclooxygenase Inhibitors Regulate the Expression of a TGF-β Superfamily Member That Has Proapoptotic and Antitumorigenic Activities

Baek, Seung Joon; Kim, Kyung Soo; Nixon, Jennifer B.; Wilson, Leigh C.; Eling, Thomas E.

doi:10.1124/mol.59.4.901

Cited by 368 publications

(461 citation statements)

References 28 publications

(34 reference statements)

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“…In addition to COX-2, a number of alternative targets have been implicated in the chemopreventive action of NSAIDs, including Bcl-2, NF-kB, NAG-1 and PPARd (Kopp and Ghosh, 1994;He et al, 1999;McEntee et al, 1999;Baek et al, 2001), suggesting that various distinct molecular pathways may play a role in the antitumour effects of these drugs. The present study provides in vivo and in vitro evidence that the b-catenin/TCF-4-signalling pathway is a target of sulindac.…”

Section: Discussionmentioning

confidence: 99%

Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

et al. 2004

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal antiinflammatory drugs appear to inhibit the initial stages of the adenoma -carcinoma sequence, suggesting a link to the APC/b-catenin/ TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) b-catenin and b-catenin/TCF-mediated transcription was investigated. Nuclear b-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on b-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear b-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated b-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated b-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear b-catenin localisation and b-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs. . Also, in patients with familial adenomatous polyposis (FAP), an autosomal dominantly inherited disorder characterised by the development of numerous colorectal adenomas at a young age, the NSAIDs sulindac and indomethacin can cause regression of adenomas (Giardiello et al, 1993;Nugent et al, 1993;Spagnesi et al, 1994;Hirota et al, 1996;Winde et al, 1997;Picariello et al, 1998). The chemopreventive effect of NSAIDs appears mediated by the induction of apoptosis and cell cycle arrest (Pasricha et al, 1995;DuBois and Smalley, 1996;Piazza et al, 1997;Keller et al, 1999;Shiff and Rigas, 1999). The molecular mechanisms underlying these biological effects are not completely understood. Nonsteroidal anti-inflammatory drugs inhibit the enzymatic activity of cyclooxygenase (COX)-1 and -2, enzymes that convert arachidonic acid into prostaglandins (Shiff and Rigas, 1999). However, COX-independent mechanisms may also play a role, since NSAIDs inhibit the growth of colon cancer cell lines lacking COX-2 expression (Hanif et al, 1996;Zhang et al, 1999;Smith et al, 2000).Oncogenic activation of the Wnt-signalling pathway by mutations in Adenomatous polyposis coli (APC) or b-catenin, which results in the accumulation and nuclear translocation of b-catenin and in b-catenin/TCF4-regulated transcription of TCF target genes, is mandatory for the initial neoplastic transformation of intestinal epithelium (reviewed in Kinzler and Vogelstein, 1996...

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Section: Discussionmentioning

confidence: 99%

Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

et al. 2004

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“…Blots were blocked with 5% skim milk in Trisbuffered saline containing 0.1% Tween 20 (TBS-T). The blots were incubated for 1 h at room temperature with a polyclonal anti-human NAG-1 antibody (1:1,000 dilution) (Baek et al, 2001), in 5% skim milk in TBS-T.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…We also determined whether human NAG-1 antibody (Baek et al, 2001) specifically recognises canine NAG-1 protein. As shown in Fig.…”

Section: Tissue Distribution Of Canine Nag-1mentioning

confidence: 99%

“…A number of NSAIDs reduced cell proliferation rate, inhibited cell cycle progression and induced apoptosis in colorectal cancer cells ( Goldberg et al, 1996, Baek et al, 20012002b). Administration of the NSAID sulindac dramatically reduced the number of tumours in the intestinal tract of Min mice, a strain containing a fully penetrant dominant mutation in the Apc gene that leads to the development of gastrointestinal adenomas (Boolbol et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we identified NAG-1 (NSAID-activated gene), a member of the TGF-β superfamily, by polymerase chain reaction (PCR)-based subtractive hybridisation from an indomethacininduced library in human colorectal cancer cells (Baek et al, 2001). Induction of NAG-1, subsequently, was observed following treatment with a number of other NSAIDs, including cyclooxygenase-1 (COX-1) specific, COX-2 specific and conventional NSAIDs (Baek et al, 2002b).…”

Section: Introductionmentioning

confidence: 99%

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Molecular characterisation of canine nonsteroidal anti-inflammatory drug-activated gene (NAG-1)

Yamaguchi

Whitlock

Liggett

et al. 2008

The Veterinary Journal

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Nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1), a divergent member of the transforming growth factor β superfamily, was previously identified as a gene induced by several anti-tumorigenic compounds, including NSAIDs and peroxisome proliferator-activated receptor γ (PPARγ) ligands in humans. In this study, canine NAG-1 was characterised from a canine genomic database. Gene induction by some NSAIDs and PPARγ ligands was demonstrated in canine osteosarcoma cell lines. Phylogenetic analysis indicates that canine NAG-1 is more homologous with the corresponding mouse and rat genes than with human NAG-1. Expression of canine NAG-1 was increased by treatment with piroxicam and SC-560 (NSAIDs) and the PPARγ ligand rosiglitazone. This study demonstrates that canine NAG-1 is up-regulated by some anti-tumorigenic compounds in osteosarcoma cell lines and may provide an important target of chemotherapy in canine cancer.

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Polarized Light Microscopic Analysis of Bone Formation After Inhibition of Cyclooxygenase 1 and 2

Retamoso

Montagner

Camargo

et al. 2010

The Anatomical Record

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Potassium diclofenac is a potent nonsteroidal anti-inflammatory drug (NSAID) and COX isoforms (COX-1 and COX-2) inhibitor. Quantitative analysis of birefringence with polarized light microscopy is a useful method to investigate the macromolecular orientation and organization of collagen fibers in connective tissues. The aim of this research was to analyze the collagen structure and maturation in bone formed after potassium diclofenac administration, during first molar orthodontic movement. Sixty Wistar rats were divided in two equal groups (N ¼ 30): control (C) and potassium diclofenac (PD). The animals in Group C received 0.9% saline solution and the PD group received potassium diclofenac Cataflam V R (5 mg/kg). Animals were sacrificed 3, 7, or 14 days after a NiTi unilateral closed-coil spring was stretched between the upper right first molar and the incisors. The first molar area was fixed, decalcified, and histologically processed using picrosirius pigment. The collagen birefringence of bone turnover was analyzed by phase retardation. Two-way ANOVA and Tukey's test showed that optical retardation was influenced by time and treatment. There was increase in the collagen organization over time. On the third day, the C group showed better collagen organization than the PD group. Potassium diclofenac interfered in collagen maturation, reducing fibril organization in the initial phase of orthodontic movement. Anat Rec,

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Cyclooxygenase Inhibitors Regulate the Expression of a TGF-β Superfamily Member That Has Proapoptotic and Antitumorigenic Activities

Cited by 368 publications

References 28 publications

Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

Molecular characterisation of canine nonsteroidal anti-inflammatory drug-activated gene (NAG-1)

Polarized Light Microscopic Analysis of Bone Formation After Inhibition of Cyclooxygenase 1 and 2

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