The C-terminal flanking peptide (CTFP) of progastrin inhibits apoptosis via a PI3-kinase-dependent pathway

Patel, Oneel; Marshall, Kathryn M.; Bramante, Gianni; Baldwin, Graham S.; Shulkes, Arthur

doi:10.1016/j.regpep.2010.08.005

Cited by 6 publications

(6 citation statements)

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“…Progastrin(6–80) has been shown to exert antiapoptotic effects in epithelial cell lines in vitro, and inhibition of MAPK and PI3K pathways attenuated this antiapoptotic effect. 29,30 However, inhibition of the MAPK pathway in our studies did not attenuate progastrin-mediated myofibroblast proliferation. Because pharmacologic inhibition of CCK-2R did not result in decreased proliferation (Figure 3 A ) and because we did not detect the presence of this receptor in CCD18Co cells by nested RT-PCR (Figure 2 B ), it is unlikely that signaling via the CCK-2 receptor is responsible for the effects of progastrin on myofibroblasts in vitro.…”

Section: Discussioncontrasting

confidence: 58%

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

et al. 2013

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BACKGROUND & AIMS Many colon cancers produce the hormone progastrin, which signals via autocrine and paracrine pathways to promote tumor growth. Transgenic mice that produce high circulating levels of progastrin (hGAS) have increased proliferation of colonic epithelial cells and are more susceptible to colon carcinogenesis than control mice. We investigated whether progastrin affects signaling between colonic epithelial and myofibroblast compartments to regulate tissue homeostasis and cancer susceptibility. METHODS Colonic myofibroblast numbers were assessed in hGAS and C57BL/6 mice by immunohistochemistry. Human CCD18Co myofibroblasts were incubated with recombinant human progastrin (rhPG)(1–80) for 18 hours, and proliferation was assessed in the presence of pharmacologic inhibitors. The proliferation of human HT29 colonic epithelial cells was assessed after addition of conditioned media from CCD18Co cells incubated with progastrin. The effects of the insulin-like growth factor (IGF)-I receptor antagonist AG1024 were investigated in cultured HT29 cells and on the colonic epithelium of hGAS mice compared with mice that did not express transgenic progastrin (controls). RESULTS The colonic mucosa of hGAS mice contained greater numbers of myofibroblasts that expressed α–smooth muscle actin and vimentin than controls. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1–80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. CCD18Co cells secreted IGF-II in response to rhPG(1–80), and conditioned media from CCD18Co cells that had been incubated with rhPG(1–80) increased the proliferation of HT29 cells. The colonic epithelial phenotype of hGAS mice (crypt hyperplasia, increased proliferation, and altered proportions of goblet and enteroendocrine cells) was inhibited by AG1024. CONCLUSIONS Progastrin stimulates colonic myofibroblasts to release IGF-II, which increases proliferation of colonic epithelial cells. Progastrin might therefore alter colonic epithelial cells via indirect mechanisms to promote neoplasia.

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Section: Discussioncontrasting

confidence: 58%

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

et al. 2013

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“…CTFP was able to stimulate proliferation in the gastric carcinoma cell line A c c e p t e d M a n u s c r i p t AGS (Figure 2A), but not in the colonic carcinoma cell line DLD-1 (Figure 2B), while enhancing migration in both AGS and DLD-1 cells (Figure 3). Patel et al showed that inhibition of apoptosis by CTFP in AGS cells was dependent on the PI3-kinase pathway [30]. CTFP and Ggly both decreased cell death in AGS cells (Figure 4A), but did not significantly affect survival of DLD-1 cells (Figure 4B).…”

Section: Discussionmentioning

confidence: 92%

“…CTFP has previously been reported to inhibit apoptosis in AGS cells at 10 nM and 100 nM [30]. Mutant and scrambled forms of CTFP were used to determine if this activity was specific to CTFP, or was a non-specific effect.…”

Section: Ctfp Protects Against Serum-starvation Induced Ags Cell Deathmentioning

confidence: 99%

“…CTFP activates MAP-kinase signaling and stimulates both proliferation and migration in non-transformed gastric epithelial cells (IMGE-5) as well as stimulating proliferation in gastric (LIM1839) and colonic carcinoma cell lines (SW1222, HCT-15) [35]. Patel et al showed that inhibition of apoptosis by CTFP in human gastric cancer (AGS) cells was dependent on the PI3-kinase pathway [30].…”

Section: Introductionmentioning

confidence: 99%

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The C-terminal flanking peptide of progastrin induces gastric cell apoptosis and stimulates colonic cell division in vivo

et al. 2013

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“…; Patel et al . ). These actions can be the result of crosstalk between the NF‐κB β‐catenin through Wnt ligands and Notch signalling pathways (Pannequin et al .…”

Section: Introductionmentioning

confidence: 97%

Novel roles of gastrin

Dimaline

Varró

2014

The Journal of Physiology

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The existence of the hormone gastrin in the distal stomach (antrum) has been known for almost 110 years, and the physiological function of this amidated peptide in regulating gastric acid secretion via the CCK2 receptor is now well established. In this brief review we consider important additional roles of gastrin, including regulation of genes encoding proteins such as plasminogen activator inhibitors and matrix metalloproteinases that have important actions on extracellular matrix remodelling. These actions are, at least in part, effected by paracrine signalling pathways and make important contributions to maintaining functional integrity of the gastric epithelium. Recent studies also provide support for the idea that gastrin, in concert with other hormones, could potentially contribute a post-prandial incretin effect. We also review recent developments in the biology of other gastrin gene products, including the precursor progastrin, which causes proliferation of the colonic epithelium and in certain circumstances may induce cancer formation. Glycine-extended biosynthetic processing intermediates also have proliferative effects in colonic mucosa and in some oesophageal cancer cell lines. Whether these additional gene products exert their effects through the CCK2 receptor or a separate entity is currently a matter of debate.

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The C-terminal flanking peptide (CTFP) of progastrin inhibits apoptosis via a PI3-kinase-dependent pathway

Cited by 6 publications

References 51 publications

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

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

The C-terminal flanking peptide of progastrin induces gastric cell apoptosis and stimulates colonic cell division in vivo

Novel roles of gastrin

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