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COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer.

Yao M, Song DH, Rana B, Wolfe MM - Br. J. Cancer (2002)

Bottom Line: Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398.Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase.Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells.

View Article: PubMed Central - PubMed

Affiliation: Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, 605 Albany Street, Room 504, Boston, Massachusetts, MA 02118, USA.

ABSTRACT
Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

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COX-2 promoter activity, COX-2 protein and prostaglandin synthesis induced by gastrin-17. (A) COX-2 promoter activity, (B) protein expression, and (C) change of prostaglandin levels in MC-26 cells in response to gastrin. *P<0.05, **P<0.01.
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fig5: COX-2 promoter activity, COX-2 protein and prostaglandin synthesis induced by gastrin-17. (A) COX-2 promoter activity, (B) protein expression, and (C) change of prostaglandin levels in MC-26 cells in response to gastrin. *P<0.05, **P<0.01.

Mentions: To study whether G-17 is capable of inducing COX-2 transcription, cells were transiently transfected with a COX-2 promoter luciferase construct, and luciferase assays were performed, as described above. COX-2 promoter activity was induced approximately two-fold in transfected cells incubated in presence of G-17 (100 nM) at 24 h. In addition, COX-2 protein expression was significantly increased in MC-26 cells incubated in the presence 10, 20, 50 and 100 nM G-17 at 24 h. When cells were incubated with 20 nM G-17, levels of PGE2, the major product of cyclo-oxygenase, were significantly increased at 24 h (215.9±13.6 pg well−1 vs 170.8±27.9 pg well−1, P<0.05) and 48 h (350.8±39.7 pg well−1 vs 272.2±35.6 pg well−1, P<0.05) (Figure 5Figure 5


COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer.

Yao M, Song DH, Rana B, Wolfe MM - Br. J. Cancer (2002)

COX-2 promoter activity, COX-2 protein and prostaglandin synthesis induced by gastrin-17. (A) COX-2 promoter activity, (B) protein expression, and (C) change of prostaglandin levels in MC-26 cells in response to gastrin. *P<0.05, **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376154&req=5

fig5: COX-2 promoter activity, COX-2 protein and prostaglandin synthesis induced by gastrin-17. (A) COX-2 promoter activity, (B) protein expression, and (C) change of prostaglandin levels in MC-26 cells in response to gastrin. *P<0.05, **P<0.01.
Mentions: To study whether G-17 is capable of inducing COX-2 transcription, cells were transiently transfected with a COX-2 promoter luciferase construct, and luciferase assays were performed, as described above. COX-2 promoter activity was induced approximately two-fold in transfected cells incubated in presence of G-17 (100 nM) at 24 h. In addition, COX-2 protein expression was significantly increased in MC-26 cells incubated in the presence 10, 20, 50 and 100 nM G-17 at 24 h. When cells were incubated with 20 nM G-17, levels of PGE2, the major product of cyclo-oxygenase, were significantly increased at 24 h (215.9±13.6 pg well−1 vs 170.8±27.9 pg well−1, P<0.05) and 48 h (350.8±39.7 pg well−1 vs 272.2±35.6 pg well−1, P<0.05) (Figure 5Figure 5

Bottom Line: Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398.Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase.Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells.

View Article: PubMed Central - PubMed

Affiliation: Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, 605 Albany Street, Room 504, Boston, Massachusetts, MA 02118, USA.

ABSTRACT
Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E2, the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

Show MeSH
Related in: MedlinePlus