A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells

Sheng, GG; Shao, Jinyi; Sheng, Hongmiao; Hooton, EB; Pc, Isakson; Jd, Morrow; Coffey, R J; Dubois, R. N.; Beauchamp, R. Daniel

doi:10.1016/s0016-5085(97)70007-6

Cited by 175 publications

(133 citation statements)

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“…Treatment of rat intestinal epithelial cells with TGFb causes transient induction of COX-2 and increased prostaglandin production (Gilbert et al, 1994a,b;Sheng et al, 1997b). In the present report, we have shown a dramatic increase in both COX-2 mRNA and protein, along with increase in production of prostacyclin in RIE-Tr cells after prolonged TGF-b1 treatment.…”

Section: Discussionsupporting

confidence: 64%

“…We have previously shown that non-transformed RIE-1 cells were unable to grow in Matrigel (basement membrane) and underwent apoptosis by 4 days after plating in the Matrigel. In contrast, Ras-transformed RIE cells readily formed colonies in Matrigel (Sheng et al, 1997a). RIE-Tr cells exhibited the ability to grow in Matrigel and to rapidly form colonies in Matrigel ( Figure 3a).…”

Section: Neoplastic Transformation Of Rie-tr Cellsmentioning

confidence: 99%

“…The rate of TbRII protein synthesis was decreased by 63% in the RIE-Tr cells as compared with the rate in RIE-1 cells, as determined by metabolic labeling experiment ( Figure 4c). We previously reported that TGF-b1 treatment downregulates the expression of cyclin D1, and induces the expression of COX-2 in RIE cells (Ko et al, 1995(Ko et al, , 1998Sheng et al, 1997b). To determine whether the targeted genes are still regulated by TGF-b1 treatment in RIE-Tr cells the regulation of cyclin D1 and COX-2 proteins was analysed.…”

Section: Transformation Of Intestinal Epithelial Cell and Tgf-b1mentioning

confidence: 99%

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Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

et al. 1999

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The precise role of TGF-b in colorectal carcinogenesis is not clear. The purpose of this study was to determine the phenotypic alterations caused by chronic exposure to TGF-b in non-transformed intestinal epithelial (RIE-1) cells. Growth of RIE-1 cells was inhibited by 475% following TGF-b1 treatment for 7 days, after which the cells resumed a normal growth despite the presence of TGF-b1. These`TGF-b-resistant' cells (RIE-Tr) were continuously exposed to TGF-b for 450 days. Unlike the parental RIE cells, RIE-Tr cells lost contact inhibition, formed foci in culture, grew in soft agarose. RIE-Tr cells demonstrated TGF-b-dependent invasive potential in an in vitro assay and were resistant to Matrigel and Na-butyrate-induced apoptosis. The RIETr cells were also tumorigenic in nude mice. The transformed phenotype of RIE-Tr cells was associated with a 95% decrease in the level of the type II TGF-b receptor (TbRII) protein, a 40-fold increase in cyclooxygenase-2 (COX-2) protein, and 5.9-fold increase in the production of prostacyclin. Most RIE-Tr subclones that expressed low levels of TbRII and high levels of COX-2 were tumorigenic. Those subclones that express abundant TbRII and low levels of COX-2 were not tumorigenic in nude mice. A selective COX-2 inhibitor inhibited RIE-Tr cell growth in culture and tumor growth in nude mice. The reduced expression of TbRII, increased expression of COX-2, and the ability to form colonies in Matrigel were all reversible upon withdrawal of exogenous TGFb1 for the RIE-Tr cells.

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Section: Discussionsupporting

confidence: 64%

Section: Neoplastic Transformation Of Rie-tr Cellsmentioning

confidence: 99%

Section: Transformation Of Intestinal Epithelial Cell and Tgf-b1mentioning

confidence: 99%

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Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

et al. 1999

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“…For example, overexpression of COX-2 has been shown to contribute to tumorigenicity of ras-transformed intestinal epithelial cells. 26 It has also been demonstrated that oncogenes such as RAS and c-MYB positively regulate COX-2. 10,13,27 In contrast, tumor suppressor genes such as p53 negatively regulate COX-2.…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer

Kikuchi

Itoh

Toyota

et al. 2001

Intl Journal of Cancer

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Cyclooxygenase 2 plays a critical role in the development of gastrointestinal cancers in both human and animal models. About 80% of the gastric cancer showed a high level of expression of cyclooxygenase 2, but a subset of cases do not express without unknown reason. Aberrant methylation of CpG island of COX-2 was examined by using a series of gastric cancer cell lines and primary gastric cancers. Two out of 8 cell lines (25%) and 11 out of 93 (12%) primary cancers showed aberrant methylation of the 5 region of COX-2. Methylation of COX-2 was closely associated with loss of expression and treatment of methylation inhibitor, 5-deoxy-2 -azacytidine restored the expression of COX-2. A combined treatment of 5-deoxy-2 -azacytidine and a histone deacetylese inhibitor, trichostatin A, restored re-expression of the gene synergistically and chromatin immunoprecipitation analysis revealed that histone of methylated COX-2 promoter is deacetylated, indicating the role of cytosine methylation and histone deacetylation in the silencing of the gene. These results indicate that a subset of gastric cancer with COX-2 methylation evolves through the pathway that is independent of COX-2 expression and that COX-2 inhibitor may not be useful to induce apoptosis in these cases. © 2002 Wiley-Liss, Inc. Key words: NSAID; chromatin, histone acetylation; methylator phenotypeCyclooxygenases are rate-limiting enzymes in the synthesis of prostaglandins. Two isoforms, cyclooxygenase 1 (COX-1) and cyclooxyganese 2 (COX-2), are involved in this process, 1 and COX-1 is the constitutive isoform expressed in various types of tissues, whereas COX-2 is an inducible enzyme. Overexpression of COX-2 has been reported in multiple types of gastrointestinal malignancies including colorectal, gastric, esophageal and pancreatic cancers. [2][3][4][5][6] Studies that used animal models indicate that COX-2 plays important roles in cell adhesion, apoptosis and angiogenesis. 7,8 Numerous epidemiological studies suggest that the use of nonsteroidal anti-inframatory drugs (NSAIDs) decreases the incidence of gastrointestinal cancers and COX-2 is recognized as a major target of NSAIDs. 9 Inhibition of COX-2 by NSAIDS or COX-2-specific inhibitors causes cell death in cancer cells, 10,11 indicating that COX-2 is an important molecular target for prevention and therapy in gastrointestinal cancers.The precise mechanism of how COX-2 expression is controlled remains unclear. Recent studies indicate that both positive and negative regulators are involve in the regulation of COX-2 expression. Among these, a signal pathway related to RAS/MAP kinase is demonstrated to up-regulate COX-2. 12 In addition, this pathway up-regulates COX-2 by increasing the stability of the transcript. 13 On the other hand, p53 has been demonstrated to down-regulate COX-2. 14 Therefore, activation of COX-2 can be partly explained by the alteration of several known oncogenes and tumor suppressor genes. Several lines of evidence suggest that COX-2 expression is not exclusive in all the tumors analyzed...

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“…When Min mice were treated with celecoxib or the conventional NSAID piroxicam, the number of tumors per animal was significantly reduced. 9 Knocking out the Cox-2 gene resulted in an 8-fold reduction in the intestinal tumor burden. 10 However, the Cox-1-deficient Min mice exhibit similar decreases in intestinal tumorigenesis as Cox-2-nulled Min mice.…”

Section: Cyclooxygenase-deficient Micementioning

confidence: 99%

Is COX-2 inhibition a panacea for cancer prevention?

Vainio

2001

Int. J. Cancer

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The epidemiologic evidence and rodent studies suggest strongly that nonselective inhibitors of cyclooxygenase (COX) enzymes such as aspirin, inhibiting both COX-1 and COX-2 isoforms, reduce the incidence of and mortality from intestinal tumors. Genetically manipulated animals show that both Cox-1 and Cox-2 disruptions decrease the tumor yield, both in genetically predisposed and in carcinogentreated mice. The mechanisms by which COX-1 and COX-2 deficiency decrease tumorigenesis are still unknown. Cox-2 overexpression increased the tumor yield in mammary glands of the multiparous, but not virginal female transgenic mice using the murine mammary tumor virus promoter. The Cox-2 protein was strongly induced during pregnancy and lactation. These data suggest that Cox-2 overexpression may be an important target for cancer chemoprevention. This finding was supported by the observed cancer-preventive effects of the COX-2-specific inhibitors in humans and in rodents. However, based on the available data, we cannot totally attribute the cancer preventive effects of nonsteroidal antiinflammatory drugs (NSAIDs) to COX-2 alone-even COX-1 may have an important role in cancer prevention as suggested by the Cox-1-deficient Min mice. It is likely that COX-1 plays a more important role in NSAID-induced toxicity in humans, such as in gastric ulcer formation-but inhibition of COX-2 may not be without toxic manifestations either, as suggested by the poor survival of the Cox-2-nulled mice. Combinations of COX-2 inhibitors with other agents that target other pathways in carcinogenesis may be a more efficacious and a less toxic strategy in cancer chemoprevention.

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A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells

Cited by 175 publications

References 1 publication

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer

Is COX-2 inhibition a panacea for cancer prevention?

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