Involvement of neurotensin in cancer growth: Evidence, mechanisms and development of diagnostic tools

Carraway, Robert E.; Plona, Ann M.

doi:10.1016/j.peptides.2006.04.030

Cited by 97 publications

(100 citation statements)

References 74 publications

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“…The peptide neurotensin (NT), 2 identified and characterized by Carraway and Leeman (1) from bovine hypothalamus, is produced in the brain and in enteroendocrine cells localized predominantly in the jejunum and ileum. The gastrointestinal effects of NT include facilitation of fatty acid translocation from the intestinal lumen, regulation of gut motility, and stimulation of the growth of normal gut mucosa as well as other tissues such as the adrenal gland, hepatocytes, and fibroblasts (2,3).…”

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confidence: 99%

“…The gastrointestinal effects of NT include facilitation of fatty acid translocation from the intestinal lumen, regulation of gut motility, and stimulation of the growth of normal gut mucosa as well as other tissues such as the adrenal gland, hepatocytes, and fibroblasts (2,3). NT also stimulates growth of certain pancreatic, colonic, and prostatic cancers bearing NT receptors (2,3), and recently a novel role of NT as a proinflammatory peptide has been demonstrated in the gut (4,5). Together, these studies identify NT as an important intestinal hormone in normal physiologic functions and, furthermore, as a potential mediator of pathologic effects such as tumor growth and inflammation.…”

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confidence: 99%

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PKD1, PKD2, and Their Substrate Kidins220 Regulate Neurotensin Secretion in the BON Human Endocrine Cell Line

Chen

Townsend

et al. 2008

Journal of Biological Chemistry

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Neurotensin (NT) is a gut peptide that plays an important role in gastrointestinal secretion, motility, and growth as well as the proliferation of NT receptor-positive cancers. Protein kinase D (PKD) family members (PKD1, 2, and 3) have been identified as important regulators of secretory transport at the trans-Golgi network. Previously, we showed that PKD1 contributes to stimulated NT secretion; however, the mechanisms are not entirely clear. Here, we show that Kidins220, which is a substrate of PKD proteins in neuroendocrine cells, is localized in the ends of the processes of BON cells, similar to the expression pattern of NT vesicles, and translocates to the membrane and large vesicle-like structures formed in response to phorbol 12-myristate 13-acetate treatment. The short hairpin RNA targeting Kidins220 inhibits NT secretion in parental BON cells or BON cells stably expressing the gastrin-releasing peptide receptor treated with either phorbol 12-myristate 13-acetate or bombesin, respectively. Furthermore, we demonstrate that endogenous PKD1, PKD2, and Kidins220 co-exist with NT-containing vesicles. Overexpression of the kinase-dead PKD1 abrogates Kidins220 expression and NT vesicle formation. Our data establish a physiological link between the PKD/Kidins220 pathway and NT-containing vesicles and suggest the role of this pathway in the regulation of hormone secretion. Because NT is an important gut hormone that affects secretion, inflammation, and both normal and tumor cell growth, our findings identify a novel signaling pathway that may be amenable to drug targeting for clinical applications.The peptide neurotensin (NT), 2 identified and characterized by Carraway and Leeman (1) from bovine hypothalamus, is produced in the brain and in enteroendocrine cells localized predominantly in the jejunum and ileum. The gastrointestinal effects of NT include facilitation of fatty acid translocation from the intestinal lumen, regulation of gut motility, and stimulation of the growth of normal gut mucosa as well as other tissues such as the adrenal gland, hepatocytes, and fibroblasts (2, 3). NT also stimulates growth of certain pancreatic, colonic, and prostatic cancers bearing NT receptors (2, 3), and recently a novel role of NT as a proinflammatory peptide has been demonstrated in the gut (4, 5). Together, these studies identify NT as an important intestinal hormone in normal physiologic functions and, furthermore, as a potential mediator of pathologic effects such as tumor growth and inflammation.Previously, we established and characterized a novel endocrine cell line, BON, derived from a human pancreatic carcinoid tumor (6). BON cells synthesize and secrete NT peptide and process the NT peptide in a manner analogous to that of enteroendocrine cells in the small bowel, thus serving as a useful model for enteroendocrine cell secretion (6). Also, BON cells have been instrumental in delineating signaling molecules that contribute to the stimulated secretion of hormones and amines from carcinoid tumors (7). Focusing on t...

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confidence: 99%

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confidence: 99%

PKD1, PKD2, and Their Substrate Kidins220 Regulate Neurotensin Secretion in the BON Human Endocrine Cell Line

Chen

Townsend

et al. 2008

Journal of Biological Chemistry

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“…They stimulate cancer cell growth (21), mainly through binding to NTSR1, that is overexpressed in many cancer cell lines (51). NTSR1 expression is also associated with a poor prognosis in human lung cancer (8,9).…”

Section: Discussionmentioning

confidence: 99%

“…In the periphery, it exerts endocrine and paracrine actions, especially in the homeostasis of intestinal functions (19). Neurotensin is also implicated in tumor progression, including proliferation of various types of human cancer lines (colon, prostate, lung, pancreas, breast), especially through its ligation to NTSR1 (20)(21)(22)(23)(24).…”

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confidence: 99%

Differential Expression of Neurotensin and Specific Receptors, NTSR1 and NTSR2, in Normal and Malignant Human B Lymphocytes

Saada

Marget

Fauchais

et al. 2012

The Journal of Immunology

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Neurotensin, a neuropeptide growth factor, and its two specific neurotensin receptors, NTSR1 and NTSR2, were shown to be expressed by human B cell lines. Another NTSR, sortilin, which is common to neurotensin and neurotrophins, was also detected as we have previously described. Neurotensin was functional in B cell lines; it induced their proliferation and inhibited apoptosis induced by serum deprivation or Fas activation. Quantitative study of gene expression in two malignant B cell diseases showed that NTSR2 was overexpressed, NTSR1 decreased, and neurotensin was unexpressed in B cell leukemia patient’s cells, as compared with healthy B cells. However, these expressions did not significantly change in large diffuse B cell lymphoma lymph nodes compared with benign ones. This study points out that neurotensin and its two specific receptors are expressed in human B lymphocytes. Such expressions were not described, and their relationship in B cell diseases, especially in chronic B cell leukemia, needs to be considered further in regard to these findings.

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“…Similar to other G-protein-coupled receptors, stimulated NTR1 activates multiple pathways, namely, mobilization of intracellular Ca 2þ , production of cyclic AMP and GMP, and formation of inositol triphosphate, resulting in important physiologic responses in both the central nervous system and periphery. However, it has been shown that neurotensin has significant stimulatory activity in several human neoplastic tissues (13)(14)(15). For example, NTR1 is expressed in 91% of invasive ductal breast cancer cases (16), and its expression is associated with the grade and size of the tumor and its invasive potential (17).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Neurotensin Receptor 1 Selectively Sensitizes Prostate Cancer to Ionizing Radiation

et al. 2011

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Radiotherapy combined with androgen depletion is generally successful for treating locally advanced prostate cancer. However, radioresistance that contributes to recurrence remains a major therapeutic problem in many patients. In this study, we define the high-affinity neurotensin receptor 1 (NTR1) as a tractable new molecular target to radiosensitize prostate cancers. The selective NTR1 antagonist SR48692 sensitized prostate cancer cells in a dose-and time-dependent manner, increasing apoptotic cell death and decreasing clonogenic survival. The observed cancer selectivity for combinations of SR48692 and radiation reflected differential expression of NTR1, which is highly expressed in prostate cancer cells but not in normal prostate epithelial cells. Radiosensitization was not affected by androgen dependence or androgen receptor expression status. NTR1 inhibition in cancer cell-attenuated epidermal growth factor receptor activation and downstream signaling, whether induced by neurotensin or ionizing radiation, establish a molecular mechanism for sensitization. Most notably, SR48692 efficiently radiosensitized PC-3M orthotopic human tumor xenografts in mice, and significantly reduced tumor burden. Taken together, our findings offer preclinical proof of concept for targeting the NTR1 receptor as a strategy to improve efficacy and outcomes of prostate cancer treatments using radiotherapy. Cancer Res; 71(21);

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Involvement of neurotensin in cancer growth: Evidence, mechanisms and development of diagnostic tools

Cited by 97 publications

References 74 publications

PKD1, PKD2, and Their Substrate Kidins220 Regulate Neurotensin Secretion in the BON Human Endocrine Cell Line

PKD1, PKD2, and Their Substrate Kidins220 Regulate Neurotensin Secretion in the BON Human Endocrine Cell Line

Differential Expression of Neurotensin and Specific Receptors, NTSR1 and NTSR2, in Normal and Malignant Human B Lymphocytes

Inhibition of Neurotensin Receptor 1 Selectively Sensitizes Prostate Cancer to Ionizing Radiation

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