Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors

Richter, M.; Weiß, Martin; Weinberger, I; Fürstenberger, Gerhard; Marian, Brigitte

doi:10.1093/carcin/22.1.17

Cited by 120 publications

(79 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This effect is thought to be caused predominantly by inhibition of cyclo-oxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis (Richter et al, 2001;Won et al, 1998). However, recent studies have suggested that COX-independent pathways may contribute considerably to these anti-proliferative effects.…”

Section: Discussionmentioning

confidence: 99%

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

et al. 2002

View full text Add to dashboard Cite

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-b 1 , increased the expression of PKCd and PKCZ, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE 2 receptor antagonists could not reverse the inhibition effect on PKCb 1 by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCb 1 attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21 waf1/cip1 . Inhibition of PKCb 1 -mediated overexpression of p21 waf1/cip1 partially reduced the anti-apoptotic effect of PKCb 1 . The down-regulation of PKCb 1 provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCb 1 act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

et al. 2002

View full text Add to dashboard Cite

show abstract

“…These cells express high levels of COX-2 and produce as much as 1 -2 nM PGE 2 within 24 h. Their VEGF expression was higher than that of LT97 cells. As PG production could not be completely blocked by SC236, a highly specific COX-2 inhibitor (Richter et al, 2001), we cannot prove that the effect was PG dependent. Neither could stimulation of VEGF expression be confirmed using LT97 cells overexpressing COX-2 from an adenoviral vector.…”

Section: Discussionmentioning

confidence: 84%

“…As cell line models, we have used LT97 human colorectal adenoma cells and Caco2 colorectal carcinoma cells that express only minimal amounts of COX-2 and produce little PGE 2 (Richter et al, 2001). Exposure to PGE 2 stimulated growth of the adenoma cells with an optimal concentration of 1 mM as well as in the Caco2 cells (Pai et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…VACO235 are villous adenoma cells that highly express COX-2 and secrete PGE 2 up to a concentration of 1 -2 nM into their culture supernatant (Willson et al, 1987;Richter et al, 2001). Expression of VEGF and c-fos in these cells was analysed by RT -PCR and found to be higher than that of LT97 cells ( Figure 5).…”

Section: Effects Of Sustained Pge 2 Production In Adenoma Cell Culturesmentioning

confidence: 99%

“…To answer these questions we have established the human colonic adenoma cell line LT97 from microadenomas of a polyposis patient that do not yet express COX-2 or produce PGE 2 (Richter et al, 2001). Tumour-promoting bile acids have been shown to induce expression of c-fos, COX-2 and vascular endothelial growth factor (VEGF) in these early human colonic adenoma cells (Jurek et al, 2005).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Prostaglandin E2 stimulates progression-related gene expression in early colorectal adenoma cells

Mauritz¹,

Westermayer²,

Marian³

et al. 2006

Br J Cancer

View full text Add to dashboard Cite

Upregulation of cyclooxygenase-2 (COX-2) and prostaglandin-dependent vascularisation in small adenomatous polyps is an essential part of colon carcinogenesis. To study the underlying cellular mechanisms, LT97 and Caco2 human colorectal tumour cells not expressing endogenous COX-2 were exposed to 1 mM prostaglandin E 2 (PGE 2 ) in their medium. At 30 min after addition, expression of c-fos was stimulated 5-fold and 1.3-fold, respectively, depending on the activation of both extracellular signal-regulated kinase and p38. The amount of c-jun in nuclear extracts was increased 20% in LT97 cells. Expression of COX-2 was upregulated 1.7-fold in LT97 cells and 1.5-fold in Caco2 2 h after prostaglandin (PG) addition by a p38-mediated pathway. The known PGE 2 target gene vascular endothelial growth factor (VEGF) was not modulated. Effects of sustained PGE 2 production were studied in VACO235 cells that have high endogenous COX-2 and in LT97 cells infected with an adenovirus expressing COX-2. Prostaglandin E 2 secretion into the medium was 1 -2 nM and 250 pM, respectively. Expression of both VEGF and c-fos was high in VACO235 cells. In LT97 cells, COX-2 upregulated c-fos expression and c-jun content in nuclear extracts 1.7-and 1.2-fold, respectively, in a PG-dependent way. This shows that exogenous PGE 2 as well as COX-2 overexpression affect signalling and gene expression in a way that enhances tumour progression. British Journal of Cancer (2006) Upregulation of cyclooxygenase-2 (COX-2) expression in early adenomas is an essential prerequisite of colorectal carcinogenesis. It causes elevated levels of prostaglandins (PGs) in the tissue and PG-dependent neovascularisation (Eberhart et al, 1994). Adenomatous polyps regress under therapy with non-steroidal anti-inflammatory drugs whose main cellular target is COX-2 (DuBois et al, 1996). Mice carrying a hereditary mutation in the APC gene (min-mice or transgenic DAPC-mice; (de Wind et al, 1998) develop a multitude of intestinal polyps in a COX-2 and prostaglandin E 2 (PGE 2 )-receptor-dependent way (Sonoshita et al, 2001;Seno et al, 2002;Sunayama et al, 2002). Immunohistochemical analysis of tissue sections shows that much of the COX-2 is located in connective tissue but not in the epithelial compartment of the polyps. In the pathology of human colorectal cancer, COX-2 plays a similar role and has become the main target of chemoprevention in high-risk patients (DuBois et al, 1996;Gupta and Dubois, 2001). As in the mouse models, COX-2 is mainly located in the connective tissue of human adenomatous polyps.This raises the question whether PGs produced in the microenvironment (fibroblasts, endothelial cells or macrophages) can in turn affect early premalignant cells and trigger expression of tumour-associated genes. To answer these questions we have established the human colonic adenoma cell line LT97 from microadenomas of a polyposis patient that do not yet express COX-2 or produce PGE 2 (Richter et al, 2001). Tumour-promoting bile acids have been shown to induce expression of ...

show abstract

Cyclo-oxygenase 2 inhibition in colorectal cancer therapy

Church

Fleshman

McLeod

2003

British Journal of Surgery

View full text Add to dashboard Cite

show abstract

Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors

Cited by 120 publications

References 23 publications

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Prostaglandin E2 stimulates progression-related gene expression in early colorectal adenoma cells

Cyclo-oxygenase 2 inhibition in colorectal cancer therapy

Contact Info

Product

Resources

About