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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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Western blot of cyclin D1 expression. (A) in MC-26 colon cancer tissues treated with gastrin-17 (10 nmol kg−1 h−1) in the absence or presence of NS-398 (1 and 10 mg kg−1). (B) Analysis of Western blot densitometry. *P<0.05, **P<0.01.
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fig3: Western blot of cyclin D1 expression. (A) in MC-26 colon cancer tissues treated with gastrin-17 (10 nmol kg−1 h−1) in the absence or presence of NS-398 (1 and 10 mg kg−1). (B) Analysis of Western blot densitometry. *P<0.05, **P<0.01.

Mentions: Consistent with tumour growth, cyclin D1 protein and PCNA index in tumour tissues were significantly greater in the tumour tissue of G-17 treated mice. Low-dose NS-398 (1 mg kg−1) partially attenuated gastrin-induced cyclin D1 and PCNA, while high-dose NS-398 (10 mg kg−1) significantly decreased both of them to values significantly less than unstimulated conditions (Figures 3Figure 3


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)

Western blot of cyclin D1 expression. (A) in MC-26 colon cancer tissues treated with gastrin-17 (10 nmol kg−1 h−1) in the absence or presence of NS-398 (1 and 10 mg kg−1). (B) Analysis of Western blot densitometry. *P<0.05, **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Western blot of cyclin D1 expression. (A) in MC-26 colon cancer tissues treated with gastrin-17 (10 nmol kg−1 h−1) in the absence or presence of NS-398 (1 and 10 mg kg−1). (B) Analysis of Western blot densitometry. *P<0.05, **P<0.01.
Mentions: Consistent with tumour growth, cyclin D1 protein and PCNA index in tumour tissues were significantly greater in the tumour tissue of G-17 treated mice. Low-dose NS-398 (1 mg kg−1) partially attenuated gastrin-induced cyclin D1 and PCNA, while high-dose NS-398 (10 mg kg−1) significantly decreased both of them to values significantly less than unstimulated conditions (Figures 3Figure 3

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