Neurotensin stimulates growth of colon cancer

Yoshinaga, Keigo; Evers, B. Mark; Izukura, M; Parekh, Dilipkumar; Uchida, Tatsuo; Townsend, Courtney M.; Thompson, James C.

doi:10.1016/0960-7404(92)90025-g

Cited by 48 publications

(31 citation statements)

References 29 publications

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“…Peptide containing nerve fibers may be detected in the normal rat colonic mucosa (23) and these peptides play an important role in the control of cell proliferation in normal intestinal mucosal cells (24) and are involved in cancer development (25,26). The denervation of the gut leads to profound changes in the mucosal peptide concentration (23).…”

Section: Discussionmentioning

confidence: 99%

Intrinsic denervation of the colon is associated with a decrease of some colonic preneoplastic markers in rats treated with a chemical carcinogen

Vespúcio

Turatti

Modiano

et al. 2008

Braz J Med Biol Res

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Denervation of the colon is protective against the colon cancer; however, the mechanisms involved are unknown. We tested the hypothesis that the denervated colonic mucosa could be less responsive to the action of the chemical carcinogen dimethylhydrazine (DMH). Three groups of 32 male Wistar rats were treated as follows: group 1 (G1) had the colon denervated with 0.3 mL 1.5 mM benzyldimethyltetradecylammonium (benzalkonium chloride, BAC); G2 received a single ip injection of 125 mg/kg DMH; G3 was treated with BAC + the same dose and route of DMH. A control group (Sham, N = 32) did not receive any treatment. Each group was subdivided into four groups according to the sacrifice time (1, 2, 6, and 12 weeks after DMH). Crypt fission index, ß-catenin accumulated crypts, aberrant crypt foci, and cell proliferation were evaluated and analyzed by ANOVA and the Student t-test. G3 animals presented a small number of aberrant crypt foci and low crypt fission index compared to G2 animals after 2 and 12 weeks, respectively. From the second week on, the index of ß-catenin crypt in G3 animals increased slower than in G2 animals. From the 12th week on, G2 animals presented a significant increase in cell proliferation when compared to the other groups. Colonic denervation plays an anticarcinogenic role from early stages of colon cancer development. This finding can be of importance for the study of the role of the enteric nervous system in the carcinogenic process.

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Section: Discussionmentioning

confidence: 99%

Intrinsic denervation of the colon is associated with a decrease of some colonic preneoplastic markers in rats treated with a chemical carcinogen

Vespúcio

Turatti

Modiano

et al. 2008

Braz J Med Biol Res

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“…NT modulates motility in the stomach, small bowel, and colon (3-5) and stimulates secretion in the dog jejunum (6) and human colonic mucosa (7,8). NT also stimulates growth and regeneration of the intestinal mucosa (9, 10) and has been implicated in the pathophysiology of colon cancer (11,12).…”

Section: Neurotensin (Nt)mentioning

confidence: 99%

Insulin-like Growth Factor-1 Receptor Transactivation Modulates the Inflammatory and Proliferative Responses of Neurotensin in Human Colonic Epithelial Cells

Zhao

Bakirtzi

Zhan

et al. 2011

Journal of Biological Chemistry

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sion. This is the first report to indicate that NT transactivates IGF-1R and that this response is linked to Akt phosphorylation and NF-B activation, contributing to both pro-inflammatory and tissue repair signaling pathways in response to NT in colonic epithelial cells. We propose that IGF-1R activation represents a previously unrecognized key pathway involved in the mechanisms by which NT and NTR1 modulate colonic inflammation and inflammatory bowel disease. Neurotensin (NT)4 is a 13-amino acid neuropeptide initially isolated from the bovine hypothalamus by Carraway and Leeman (1) and is highly expressed in the gastrointestinal tract (2). NT modulates motility in the stomach, small bowel, and colon (3-5) and stimulates secretion in the dog jejunum (6) and human colonic mucosa (7,8). NT also stimulates growth and regeneration of the intestinal mucosa (9, 10) and has been implicated in the pathophysiology of colon cancer (11,12).Two G-protein-coupled receptors (GPCRs) have been described for NT: a high-affinity (NTR1) and a low-affinity (NTR2) receptor (13). A third, non-GPCR has also been identified (14). Several studies underlined the importance of NTR1 in several intestinal pathologic conditions. Administration of the specific NTR1 antagonist SR 48692 to rats inhibits colonic responses to stress (15, 16) and reduces colonic secretion and inflammation mediated by Clostridium difficile toxin A (17). Increased NTR1 expression is evident in the colonic mucosa during the course of acute colitis mediated by toxin A (17), in the colons of mice with experimental colitis (18), and in humans with inflammatory bowel disease (18). In a recent study, we also showed that involvement of NT in colonic inflammation may include direct stimulation of pro-inflammatory chemoattractant IL-8 transcription in colonic epithelial cells (19).NT stimulates several intracellular signaling events, as shown in human colonic and pancreatic cell lines expressing endogenous NTR1 (20, 21). These include increased intracellular calcium release (22, 23) and activation of the MAPK family member ERK1/2 in pancreatic MIA PaCa-2 cells (24), transformed colonic adenocarcinoma HT29 cells (24), and non-transformed human colonic epithelial NCM460 cells (19). Our recent studies indicate that NT also activates the NF-B pathway (19) and the Rho family of small GTPases (25,26). Two previous studies showed that pretreatment with PKC inhibitors reduces NT-induced ERK1/2 activation in CHO cells overexpressing NTR1 (24) and in pancreatic carcinoma PANC-1 cells expressing endogenous NTR1 (27). In contrast, our laboratory and Hassan et al. have found that EGF receptor (EGFR) transactivation is involved in NT-in-

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“…NT alters motility in the stomach, small bowel, and colon (5-7), stimulates secretion in the ileum (8), pancreas (9), and the biliary tract (10), and causes Cl Ϫ secretion from human colonic mucosa (11). NT also stimulates growth and regeneration of the intestinal mucosa (12,13) and has been implicated in the pathophysiology of colon cancer (14,15).…”

mentioning

confidence: 99%

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Zhao¹,

Zhan²,

Koon³

et al. 2004

Journal of Biological Chemistry

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Expression of the neuropeptide neurotensin (NT) and its high affinity receptor (NTR1) is increased during the course of Clostridium difficile toxin A-induced acute colitis, and NTR1 antagonism attenuates the severity of toxin A-induced inflammation. We recently demonstrated in non-transformed human colonic epithelial NCM460 cells that NT treatment caused activation of a Ras-mediated MAP kinase pathway that significantly contributes to NT-induced interleukin-8 (IL-8) secretion. Here we used NCM460 cells, which normally express low levels of NTR1, and NCM460 cells stably transfected with NTR1 to identify the upstream signaling molecules involved in NT-NTR1-mediated MAP kinase activation. We found that inhibition of the epidermal growth factor receptor (EGFR) by either an EGFR neutralizing antibody or by its specific inhibitor AG1478 (0.2 M) blocked NT-induced MAP kinase activation. Moreover, NT stimulated tyrosine phosphorylation of the EGFR, and pretreatment with a broad spectrum metalloproteinase inhibitor batimastat reduced NT-induced MAP kinase activation. Using neutralizing antibodies against the EGFR ligands EGF, heparin-binding-EGF, transforming growth factor-␣ (TGF␣), or amphiregulin we have shown that only the anti-TGF␣ antibody significantly decreases NT-induced phosphorylation of EGFR and MAP kinases. Furthermore, inhibition of the EGF receptor by AG1478 significantly reduced NT-induced IL-8 promoter activity and IL-8 secretion. This is the first report demonstrating that NT binding to NTR1 transactivates the EGFR and that this response is linked to NT-mediated proinflammatory signaling. Our findings indicate that matrix metalloproteinase-mediated release of TGF␣ and subsequent EGFR transactivation triggers a NT-mediated MAP kinase pathway that leads to IL-8 gene expression in human colonic epithelial cells.Neurotensin (NT), 1 a 13-amino acid neuropeptide originally isolated by Carraway and Leeman (1) from bovine hypothalamus, is also localized in the gastrointestinal tract (2). In the small intestine NT is synthesized and secreted by specific mucosal endocrine cells in response to several different stimuli (3, 4). NT alters motility in the stomach, small bowel, and colon (5-7), stimulates secretion in the ileum (8), pancreas (9), and the biliary tract (10), and causes Cl Ϫ secretion from human colonic mucosa (11). NT also stimulates growth and regeneration of the intestinal mucosa (12, 13) and has been implicated in the pathophysiology of colon cancer (14, 15).Two G protein-coupled receptors (GPCRs) have been described for NT, a high affinity (NTR1) and a low affinity (NTR2) receptor (16). A third, non-G protein-coupled receptor has also been identified (17). Several studies underline the importance of NTR1 in several intestinal pathologic conditions. For example, administration of the specific NTR1 antagonist SR 48692 to rats inhibits colonic mucin and prostaglandin E2 secretion and mast cell activation in response to immobilization stress (18). NTR1 antagonism also reduces colonic secretion and infla...

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Neurotensin stimulates growth of colon cancer

Cited by 48 publications

References 29 publications

Intrinsic denervation of the colon is associated with a decrease of some colonic preneoplastic markers in rats treated with a chemical carcinogen

Intrinsic denervation of the colon is associated with a decrease of some colonic preneoplastic markers in rats treated with a chemical carcinogen

Insulin-like Growth Factor-1 Receptor Transactivation Modulates the Inflammatory and Proliferative Responses of Neurotensin in Human Colonic Epithelial Cells

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

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