Evidence for Autocrine Actions of Neuromedin B and Gastrin-releasing Peptide in Non-small Cell Lung Cancer

Siegfried, Jill M.; Nandigama, Krishnamachary; Davis, Autumn Gaither; Gubish, Christopher T.; Hunt, Jay D.; Shriver, Sharon P

doi:10.1006/pupt.1999.0210

Cited by 91 publications

(67 citation statements)

References 28 publications

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“…Cells were harvested after 10 min for coimmunoprecipitation to determine EGFR phosphorylation and immunoblotting to determine the expression of total EGFR, MAPK and phosphorylated MAPK. Cumulative results are shown from three independent experiments the mitogenesis of SCLC and NSCLC (Carney et al, 1987;Siegfried et al, 1999). More than 50% of SCLC and NSCLC cell lines express elevated levels of GRP or GRPR (Sorenson et al, 1982;Alexander et al, 1988;Siegfried et al, 1998;).…”

Section: Discussionmentioning

confidence: 99%

“…Sun et al reported that approximately 60% of primary prostate cancer cells express GRPR (Sun et al, 2000a). In vitro and in vivo ablation of the GRP/GRPR autocrine pathway using a GRP neutralizing antibody or bombesin analogs resulted in the inhibition of tumor growth in preclinical models of SCLC, NSCLC and prostate cancer in addition to HNSCC (Kelley et al, 1997;Siegfried et al, 1999;Plonowski et al, 2000). The therapeutic efficacy of the GRP neutralizing antibody (2A11) in SCLC is under clinical investigation (Kelley et al, 1997;Chaudhry et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…(e) In contrast, the treatment of 1483 cells with a control inhibitor (250 nm of AG-9) did not abrogate GRP-induced mitogenesis. (f) Cells derived from EGFR knockout mice or their wild-type littermates were treated with GRP (400 nm) or EGF (l0 ng/ml) or serum (20%) for 2 days followed by growth determinations using vital dye exclusion GRP serves as a mitogenic factor for fibroblasts and some cancer cells, including SCLC, NSCLC, HNSCC and glioblastoma (Carney et al, 1987;Siegfried et al, 1999;Nagakawa et al, 2000). However, the potential role of EGFR in mediating the effects of GRP has not been studied previously.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of GRPR has been shown to promote proliferation in Balb/3T3 and Rat-1 fibroblasts (Lach et al, 1995;Feldman et al, 1996). Upregulation of GRP/GRPR, or BLP receptors and their ligands have been reported in various cancers including carcinomas of the lung (both small cell lung carcinoma and nonsmall cell lung carcinoma), prostate, colon, kidney, breast and ovary, as well as glioblastoma (Halmos et al, 1995;Sharif et al, 1997;Siegfried et al, 1999;Carroll et al, 2000;Pansky et al, 2000;Rounseville & Davis, 2000;Sun et al, 2000a, b). GRP/GRPR has been shown to contribute to lung carcinogenesis by autocrine growth stimulation.…”

Section: Introductionmentioning

confidence: 99%

“…GRP/GRPR has been shown to contribute to lung carcinogenesis by autocrine growth stimulation. Both SCLC and NSCLC cells produce and secrete GRP, resulting in tumor cell proliferation (Carney et al, 1987;Siegfried et al, 1999). GRP has been reported to stimulate DNA synthesis in a glioblastoma cell line, U-373MG (Sharif et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor

et al. 2003

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Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRPinduced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-a) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-a and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor

et al. 2003

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Sensitive detection of rare cancer cells in sputum and peripheral blood samples of patients with lung cancer by preproGRP-specific RT-PCR

et al. 2001

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Impact of natural neuromedin‐B receptor variants on iron metabolism

et al. 2019

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Iron overload heritability remains partly unexplained. By performing whole exome sequencing in three patients with a clinical phenotype of hemochromatosis not accounted by known genetic risk factors, we identified in all patients rare variants predicted to alter activity of Neuromedin-B receptor (NMBR). Coding NMBR mutations were enriched in 129 patients with hereditary hemochromatosis or iron overload phenotype, as compared to ethnically matched controls, including 100 local healthy blood donors and 1000Genomes project participants (15.5% vs 5%, P = .0038 at burden test), and were associated with higher transferrin saturation in regular blood donors (P = .04). Consistently, in 191 patients with nonalcoholic fatty liver, the most common low-frequency p.L390 M variant was independently associated with higher ferritin (P = .03). In 58 individuals, who underwent oral iron challenge, carriage of the p.L390 M variant was associated with higher transferrin saturation and lower hepcidin release. Furthermore, the circulating concentration of the natural NMBR ligand, Neuromedin-B, was reduced in response to iron challenge.It was also decreased in individuals carrying the p.L390 M variant and with hemochromatosis in parallel with increased transferrin saturation. In mice, Nmbr was induced by chronic dietary iron overload in the liver, gut, pancreas, spleen, and skeletal muscle, while Nmb was downregulated in gut, pancreas and spleen. Finally, Nmb amplified holo-transferrin dependent induction of hepcidin in primary mouse hepatocytes, which was associated with Jak2 induction and abolished by the NMBR antagonist PD168368. In conclusion, NMBR natural variants were enriched in patients with iron overload, and associated with facilitated iron absorption, possibly related to a defect of iron-induced hepcidin release.

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Evidence for Autocrine Actions of Neuromedin B and Gastrin-releasing Peptide in Non-small Cell Lung Cancer

Cited by 91 publications

References 28 publications

Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor

Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor

Sensitive detection of rare cancer cells in sputum and peripheral blood samples of patients with lung cancer by preproGRP-specific RT-PCR

Impact of natural neuromedin‐B receptor variants on iron metabolism

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