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

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 E 2 , 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.

Gastrin stabilises β-catenin protein in mouse colorectal cancer cells

“…Utilising transplantable mouse CRC cells (MC-26) that express functional gastrin receptors, we have previously demonstrated the trophic properties of gastrin (Yao et al, 2002). We hypothesised that one of the mechanisms by which gastrin might exert its trophic properties may involve the multifunctional b-catenin protein.…”

“…Because these factors are important contributors to CRC growth, we sought to determine whether additional relationships might exist between gastrin and b-catenin. We have previously demonstrated the trophic properties of gastrin in mouse colorectal tumour cells , in which the peptide caused a significant incorporation of [ 3 H]thymidine at 24 and 48 h (Yao et al, 2002). Furthermore, when MC-26 cells were injected subcutaneously into BALB/C mice and treated with amidated gastrin-17 (G-17) by continuous infusion, the weight and volume of resulting tumour tissues were significantly greater than in untreated controls (Yao et al, 2002).…”

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

“…The mouse colon cancer model was established as described previously (Yao et al, 2002). MC-26 cells were harvested from subconfluent cultures by exposure to trypsin-EDTA (Life Technologies, Inc, Gaithersburg, MD, USA) for 3 min, centrifugation at 300 g for 15 min at room temperature, and then resuspension in serum-free DMEM or Hank's balanced salt solution (Life Technologies, Inc, Gaithersburg, MD, USA), to yield a final concentration of 10 5 cells ml À1 .…”

Effects of Nonselective Cyclooxygenase Inhibition with Low-Dose Ibuprofen on Tumor Growth, Angiogenesis, Metastasis, and Survival in a Mouse Model of Colorectal Cancer

“…Six-weekold male BALB/C mice and BALB/C nude mice (T-cell deficiency) were obtained from Taconic (Germantown, NY). We used our previously described mouse colon cancer model as described (17,21,22). Briefly, MC-26 model cells were harvested from subconfluent cultures by exposure to trypsin-EDTA (Life Technologies) for 3 minutes, centrifugation at 300 Â g for 15 minutes at room temperature, and then resuspension in serum-free DMEM or HBSS (Life Technologies) to yield a final concentration of 5 Â 10 6 cells/mL.…”