In addition, neu rotensin stimulates growth of the intestinal muc

In addition, neu rotensin stimulates growth of the intestinal mucosa under physiological and pathological conditions and has been found to promote cisplatin dna azoxymethane induced colon carcinogenesis in rats and mice. Neuroten sin has also been implicated in the progression of can cers of the pancreas, breast, lung, and prostate. Three subtypes of neurotensin receptors have been cloned. The high affinity NTSR1 receptor and the low affinity NTSR2 receptor both belong to the GPCR family, while the NTSR3sortilin receptor is a nonspecific receptor with a single transmembrane domain. The pharmacological and signalling properties of the NTSR2 receptor, which exerts its effects mainly in the central nervous system, are incom pletely understood, and appear to be dependent on cell type and species.

The peripheral effects of neuro tensin appear to be mediated largely by NTSR1, which activates PLCb. Experiments using a specific Inhibitors,Modulators,Libraries antagonist or knockdown of the NTSR1 using short interfering RNA suggest that NTSR1 mediates the effects of neurotensin on cancer cells, although NTSR3 sortilin, which is often coexpressed Inhibitors,Modulators,Libraries in cancer cells, may modulate NTSR1 signalling. Splice variants of the NTSR1 were recently detected in prostate cancer cell lines, however, no functional studies of these have been conducted. Recent data have suggested that the NTSR1 receptor gene may be a downstream target Inhibitors,Modulators,Libraries of the extracellular signal regulated kinase and Tcfb catenin pathways, and increased expres sion of NTSR1 during progression of colon tumorigen esis has been reported.

Neurotensin has been found to stimulate proliferation of certain colon carcinoma cell lines. Reports on intracellular Inhibitors,Modulators,Libraries signalling leading to proliferation induced by neurotensin in some other cell types have suggested the involvement of PKC dependent activation of ERK and protein Inhibitors,Modulators,Libraries kinase D. and either dependence or independence of epidermal growth factor receptor transactivation. In the pancrea tic cancer cell line Panc 1, DNA synthesis induced by neurotensin was independent of EGFR transactivation, whereas in the prostate cancer cell line PC 3, neu rotensin stimulated mitogenesis by a PKC dependent transactivation of EGFR. In colon carcinoma cell lines neurotensin has been found to activate ERK, as well as PKC, Akt, and nuclear factor B path ways. Furthermore, neurotensin induced phos phorylation and inactivation of glycogen Tubacin alpha-tubulin synthase kinase, leading to cyclin D1 expression, through mechanisms that were at least partly dependent on PKC. Neurotensin has also been found to induce a proinflammatory tumour microenvironment and pro mote cancer cell invasion through pathways that involved NFB, PKC, ERK, and the sodium proton exchanger 1.

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