High and low affinity receptors mediate growth effects of gastrin and gastrin‐Gly on DLD‐1 human colonic carcinoma cells

Ahmed, Shawn; Budai, Barna; Herédi-Szabó, Krisztina; Farkas, Judit; Tóth, Géza; Murphy, Richard F.; Lovas, Sándor

doi:10.1016/s0014-5793(03)01408-x

Cited by 23 publications

(14 citation statements)

References 39 publications

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“…In recent papers, Ahmed et al reported the importance of N and C terminal sequences in the gastrin-Gly molecule for conferring high and low affinity binding to novel receptors on colon cancer cells, respectively; these binding sites were distinct from CCK 1 R and CCK 2 R (55;56). Both the low and high affinity binding sites mediated the growth effects of gastrin-like molecules on colon cancer cells (56), suggesting that different receptor sub-types, other than CCK 1 R and CCK 2 R, may be involved in mediating growth factor effects of gastrins/progastrins. Based on our studies (6), it is possible, that the high affinity binding receptor proteins identified by Ahmed et al (6;55;56) may be ANX II.…”

Section: A Annexin-ii Is a High Affinity Receptor (Binding) Proteinmentioning

confidence: 99%

Role of Annexin-II in GI cancers: Interaction with gastrins/progastrins

Singh

2007

Cancer Letters

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The role of the gastrin peptide hormones (G17, G34) and their precursors (progastrins, PG; glyextended gastrin, G-gly), in gastrointestinal (GI) cancers has been extensively reviewed in recent years (1-3). A possible important role of progastrin peptides in colon carcinogenesis has become evident from experiments with transgenic mouse models (1;3). It is now known that growth stimulatory and co-carcinogenic effects of gastrin/PG peptides are mediated by both proliferative and anti-apoptotic effects of the peptides on target cells (4;5). Several receptor subtypes have been described that mediate growth effects of gastrin peptides (1;2). Recently, we identified Annexin II as a high affinity binding protein for gastrin/PG peptides (6). Importantly, the expression of Annexin II was required for mediating growth stimulatory effects of gastrin and PG peptides on intestinal epithelial and colon cancer cells (6), suggesting that Annexin II may represent the elusive novel receptor for gastrin/PG peptides. The importance of this finding in relation to the structure and function of Annexin II, especially in GI cancers, is described below. Since this surprising finding represents a new front in our understanding of the mechanisms involved in mediating growth effects of gastrin/PG peptides in GI cancers, our current understanding of the role of Annexin II in proliferation and metastasis of cancer cells is additionally reviewed.

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Section: A Annexin-ii Is a High Affinity Receptor (Binding) Proteinmentioning

confidence: 99%

Role of Annexin-II in GI cancers: Interaction with gastrins/progastrins

Singh

2007

Cancer Letters

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“…However, in the periphery where receptors are exposed to both circulating hormones, the main endogenous ligand is likely to be gastrin since its concentrations in plasma are about five to ten times higher than those of CCK. Neither progastrin nor the Gly-gastrins are considered to be endogenous ligands of the CCK-2 receptor, but both are reported to have their own characteristic pattern of biological activities, and these are thought to be mediated by non-CCK-1/non-CCK-2 receptors [1,112]. The term ''CCK-C receptor'' is sometimes used to describe non-CCK-1/non-CCK-2 receptors responding to progastrin-derived peptides.…”

Section: Cck-2 Receptors and Signal Transductionmentioning

confidence: 99%

Gastrin: old hormone, new functions

Dockray

Dimaline

Varró

2004

Pflugers Arch - Eur J Physiol

111

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It is exactly a century since the gastric hormone gastrin was first described as a blood-borne regulator of gastric acid secretion. The identities of the main active forms of the hormone (the "classical gastrins") and their cellular and molecular sites of action in regulating acid secretion have all attracted sustained attention. However, recent work on peptides derived from the gastrin precursor that do not stimulate acid secretion ("non-classical gastrins"), together with studies on mice over-expressing the gene, or in which the gastrin gene has been deleted, suggest hitherto unsuspected roles in regulating cell proliferation, migration, and differentiation. Moreover, microarray and proteomic studies have identified previously unsuspected target genes of the classical gastrins. Some of the newer actions have implications for our understanding of the progression to cancer in oesophagus, stomach, pancreas and colon, all of which have recently been linked in one way or another to dysfunctional signalling involving products of the gastrin gene. The present review focuses on recent progress in understanding the biology of both classical and non-classical gastrins.

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“…Furthermore, the biological effects of progastrin and gly-gastrin are not blocked by CCK-B receptor antagonists (Seva et al, 1994;Stepan et al, 1999;Baldwin et al, 2001), and amidated gastrin and gly-gastrin stimulate different downstream signalling events (Todisco et al, 2001). Potential alternative receptors for progastrin and gly-gastrin have been suggested (Seva et al, 1994;Baldwin, 1995a;Singh et al, 1995;Smith et al, 2002;Ahmed et al, 2004).…”

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confidence: 99%

Use of interfering RNA to investigate the role of endogenous gastrin in the survival of gastrointestinal cancer cells

2007

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Gastrin isoforms, acting through a variety of receptors, have proliferative and anti-apoptotic effects on gastrointestinal (GI) cancers. A small interfering RNA (siRNA) targeting the gastrin gene was used to investigate the role of endogenous gastrin in GI cancer cell survival. Downregulation of the gastrin gene in siRNA-transfected cells was measured using real-time reverse transcriptase -PCR. The most effective siRNA was tested in a panel of GI cancer cell lines at various concentrations and time points, and the effect on cell survival and apoptosis was measured using methyl thiazoyl tetrazolium (MTT) and caspase 3 activation assays. Gastrin siRNA reduced gene expression by more than 90% in a range of GI cancer cell lines. Downregulation of the gastrin gene was dose-dependent and effective over approximately 1 week in vitro. However, downregulation at the protein level was delayed by 3 -4 days. Gastrin siRNAtransfected cells showed up to a 60% reduction in growth and up to a 50% increase in apoptosis compared with control siRNAtransfected cells. The effects were most marked in the cell line with the highest constitutive level of gastrin gene expression (human metastatic colon, C170HM2) and in epidermal growth factor (EGF)-treated cells as the gastrin promoter contains an EGF-response element, gERE. The ability of the siRNAs to reduce survival of these GI cell lines is further evidence of the importance of autocrine and/or intracrine gastrin loops in GI cancer, where expression of the gastrin gene and autonomous gastrin appears widespread.

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High and low affinity receptors mediate growth effects of gastrin and gastrin‐Gly on DLD‐1 human colonic carcinoma cells

Cited by 23 publications

References 39 publications

Role of Annexin-II in GI cancers: Interaction with gastrins/progastrins

Role of Annexin-II in GI cancers: Interaction with gastrins/progastrins

Gastrin: old hormone, new functions

Use of interfering RNA to investigate the role of endogenous gastrin in the survival of gastrointestinal cancer cells

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