Stimulation of proliferation in the colorectal mucosa by gastrin precursors is blocked by desferrioxamine

Abstract

Precursors of the peptide hormone gastrin stimulate proliferation in the colorectal mucosa and promote the development of colorectal carcinoma. Gastrins bind two ferric ions selectively and with high affinity, and the biological activity of glycine-extended gastrin (Ggly) in vitro is dependent on the presence of ferric ions. The aim of the present study was to determine whether or not iron is required for biological activity of progastrin and Ggly in vivo. Rats that had undergone a colostomy were infused with Ggly, and proliferation was measured in the defunctioned rectal mucosa. Proliferation was also measured in the colonic mucosa of hGAS and MTI-Ggly mice, which, by definition, overexpress progastrin and Ggly, respectively. The requirement for iron was assessed by thrice-weekly injection of the chelating agent desferrioxamine (DFO). The proliferation index in the defunctioned rectal mucosa was significantly increased in the Ggly-infused rats, and the increase was significantly reduced after treatment with DFO. Treatment with DFO significantly reduced the crypt height and proliferation index in the colonic mucosa of hGAS and MTI-Ggly mice but had no effect on the same variables in wild-type mice. These observations are consistent with the hypothesis that the biological activity of progastrin and Ggly in vivo is dependent on the presence of ferric ions and further suggest that chelating agents may block the stimulatory effects of gastrin precursors in the development of colorectal carcinoma.

Impact of JNK1, JNK2, and ligase Itch on reactive oxygen species formation and survival of prostate cancer cells treated with diallyl trisulfide

“…Contrary to our data, in many cancer cells an increase in LIP leads to augmented cell proliferation [33,34]. Possibly, it is associated with high JNK activity in many rapidly proliferating cancer cells.…”

Progastrin-Induced Secretion of Insulin-Like Growth Factor 2 From Colonic Myofibroblasts Stimulates Colonic Epithelial Proliferation in Mice

“…17 Indeed, the identity of a progastrin receptor remains an issue of intense investigation. Recent studies have suggested that Annexin A2, 32,33 ferric ions, 34 and charged glycosaminoglycans 17 are involved.…”

Identification of the F1-ATPase at the Cell Surface of Colonic Epithelial Cells

“…Here we have shown that the F 1 -ATPase, which directly binds G-gly, is present at the plasma membrane of colonic epithelial cells in a mouse model. It is also interesting to notice that in both in vivo models (G-gly transgenic mice or G-gly infusion), treatment of the animals with DFO, a ferric ions chelating agent, reverses the proliferative effects induced by G-gly, suggesting that the biological activity of the peptide is dependent on the presence of ferric ions (34). In vitro studies confirm that G-gly binds two ferric ions necessary to its biological activity (9,25,26).…”