Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

Alifano, Marco; Souazé, Frédérique; Dupouy, Sandra; Camilleri-Broët, Sophie; Younes, Mohamad; Ahmed-Zaïd, Sadi-Menad; Takahashi, Takashi; Cancellieri, Alessandra; Damiani, Stefania; Boaron, Maurizio; Broët, Philippe; Miller, Lance D.; Gespach, Christian; Regnard, Jean François; Forgez, Patricia

doi:10.1158/1078-0432.ccr-10-0659

Cited by 100 publications

(97 citation statements)

References 35 publications

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“…Immunopositivity was found in 60% of cases. NTSR 1 positivity was associated with lower survival rates (34). In vitro, neurotensin antagonist SR48692 inhibits proliferation (35).…”

Section: Lung Cancermentioning

confidence: 99%

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Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

et al. 2014

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Learning Objectives: On successful completion of this activity, participants should be able to list and discuss (1) the presence of bombesin receptors, neurotensin receptors, or neuropeptide-Y receptors in some major tumors; (2) the perspectives offered by radiolabeled peptides targeting these receptors for imaging and therapy; and (3) the choice between agonists and antagonists for tumor targeting and the relevance of various PET radionuclides for molecular imaging.Financial Disclosure: The authors of this article have indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through October 2017.Receptors for some regulatory peptides are highly expressed in tumors. Selective radiolabeled peptides can bind with high affinity and specificity to these receptors and exhibit favorable pharmacologic and pharmacokinetic properties, making them suitable agents for imaging or targeted therapy. The success encountered with radiolabeled somatostatin analogs is probably the first of a long list, as multiple peptide receptors are now recognized as potential targets. This review focuses on 3 neuropeptide receptor systems (bombesin, neurotensin, and neuropeptide-Y) that offer high potential in the field of nuclear oncology. The underlying biology of these peptide/receptor systems, their physiologic and pathologic roles, and their differential distribution in normal and tumoral tissues are described with emphasis on breast, prostate, and lung cancers. Radiolabeled analogs that selectively target these receptors are highlighted.

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“…Immunopositivity was found in 60% of cases. NTSR 1 positivity was associated with lower survival rates (34). In vitro, neurotensin antagonist SR48692 inhibits proliferation (35).…”

Section: Lung Cancermentioning

confidence: 99%

“…Improvements in diagnosis and treatment and identification of new targets in lung cancer are urgently needed (40). The identification of NTSR 1 as a marker of poor prognosis in resected stage I lung adenocarcinoma may help decisions on adjuvant treatment (34). NTSR 1 expression also opens important perspectives for imaging and targeting.…”

Section: Lung Cancermentioning

confidence: 99%

Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

et al. 2014

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“…Our analysis also provides a structural rationale for the long-known effects of C-terminal palmitoylation reactions on G protein-coupled receptor signaling, receptor maturation, and desensitization. membrane proteins | protein stability | protein engineering | detergents N eurotensin is a 13-amino-acid peptide, which plays important roles in the pathogenesis of Parkinson's disease, schizophrenia, antinociception, and hypothermia and in lung cancer progression (1)(2)(3)(4). It is expressed throughout the central nervous system and in the gut, where it binds to at least three different neurotensin receptors (NTRs).…”

mentioning

confidence: 99%

Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli

Egloff

Hillenbrand

Klenk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

203

316

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Crystallography has advanced our understanding of G proteincoupled receptors, but low expression levels and instability in solution have limited structural insights to very few selected members of this large protein family. Using neurotensin receptor 1 (NTR1) as a proof of principle, we show that two directed evolution technologies that we recently developed have the potential to overcome these problems. We purified three neurotensin-bound NTR1 variants from Escherichia coli and determined their X-ray structures at up to 2.75 Å resolution using vapor diffusion crystallization experiments. A crystallized construct was pharmacologically characterized and exhibited ligand-dependent signaling, internalization, and wild-type-like agonist and antagonist affinities. Our structures are fully consistent with all biochemically defined ligand-contacting residues, and they represent an inactive NTR1 state at the cytosolic side. They exhibit significant differences to a previously determined NTR1 structure (Protein Data Bank ID code 4GRV) in the ligand-binding pocket and by the presence of the amphipathic helix 8. A comparison of helix 8 stability determinants between NTR1 and other crystallized G protein-coupled receptors suggests that the occupancy of the canonical position of the amphipathic helix is reduced to various extents in many receptors, and we have elucidated the sequence determinants for a stable helix 8. Our analysis also provides a structural rationale for the long-known effects of C-terminal palmitoylation reactions on G protein-coupled receptor signaling, receptor maturation, and desensitization. membrane proteins | protein stability | protein engineering | detergents N eurotensin is a 13-amino-acid peptide, which plays important roles in the pathogenesis of Parkinson's disease, schizophrenia, antinociception, and hypothermia and in lung cancer progression (1-4). It is expressed throughout the central nervous system and in the gut, where it binds to at least three different neurotensin receptors (NTRs). NTR1 and NTR2 are class A G protein-coupled receptors (GPCRs) (5, 6), whereas NTR3 belongs to the sortilin family. Most of the effects of neurotensin are mediated through NTR1, where the peptide acts as an agonist, leading to GDP/GTP exchange within heterotrimeric G proteins and subsequently to the activation of phospholipase C and adenylyl cyclase, which produce second messengers in the cytosol (5, 7). Activated NTR1 is rapidly phosphorylated and internalizes by a β-arrestin-and clathrin-mediated process (8), which is crucial for desensitizing the receptor (9). Several lines of evidence suggest that internalization is also linked to G proteinindependent NTR1 signaling (10, 11). To improve our mechanistic understanding of NTR1 and to gain additional insight into GPCR features such as helix 8 (H8), we were interested in obtaining a structure of this receptor in a physiologically relevant state.To date, by far the most successful strategy for GPCR structure determination requires the replacement of the intracel...

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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). In contrast, neurotensin is able to prevent serum starvation or IL-induced apoptosis in pancreatic cells after binding to NTSR2 or NTSR3 (52).…”

Section: Discussionmentioning

confidence: 99%

“…They include two G protein-coupled receptors: the high-affinity receptor NTSR1 and the low-affinity receptor NTSR2 (6). NTSR1 expression was recently demonstrated in aggressive malignant solid tumors such as mesothelioma (7), non-small-cell lung (8), breast (9), and head and neck squamous (10) carcinomas. NTSR2 shares 60% homology with NTSR1 (6).…”

mentioning

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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Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

Cited by 100 publications

References 35 publications

Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli

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

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