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Article: The Orexin receptors: Structural and anti-tumoral properties.

Couvineau, Alain / Nicole, Pascal / Gratio, Valérie / Voisin, Thierry

2022 Volume 13, Page(s) 931970

Abstract: At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor ... ...

Abstract	At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor isoforms named OX1R and OX2R. The orexins/OX receptors system play an important role in the central and peripheral nervous system where it controls wakefulness, addiction, reward seeking, stress, motivation, memory, energy homeostasis, food intake, blood pressure, hormone secretions, reproduction, gut motility and lipolysis. Orexins and their receptors are involved in pathologies including narcolepsy type I, neuro- and chronic inflammation, neurodegenerative diseases, metabolic syndrome, and cancers. Associated with these physiopathological roles, the extensive development of pharmacological molecules including OXR antagonists, has emerged in association with the determination of the structural properties of orexins and their receptors. Moreover, the identification of OX1R expression in digestive cancers encompassing colon, pancreas and liver cancers and its ability to trigger mitochondrial apoptosis in tumoral cells, indicate a new putative therapeutical action of orexins and paradoxically OXR antagonists. The present review focuses on structural and anti-tumoral aspects of orexins and their receptors.
MeSH term(s)	Humans ; Neoplasms/drug therapy ; Neuropeptides/metabolism ; Orexin Receptors ; Orexins ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Neuropeptides ; Orexin Receptors ; Orexins ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2022-07-28
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2022.931970
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Article ; Online: Orexins/Hypocretins and Cancer

Couvineau Alain / Nicole Pascal / Gratio Valérie / Voisin Thierry

Molecules, Vol 26, Iss 4849, p

A Neuropeptide as Emerging Target

2021 Volume 4849

Abstract: Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and ... ...

Abstract	Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.
Keywords	orexins ; neuropeptide ; GPCR ; apoptosis ; cancer ; gastroenterology ; Organic chemistry ; QD241-441
Subject code	610
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions.

Couvineau, Alain / Voisin, Thierry / Nicole, Pascal / Gratio, Valerie / Blais, Anne

World journal of gastroenterology

2021 Volume 27, Issue 44, Page(s) 7582–7596

Abstract: Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the ... ...

Abstract	Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.
MeSH term(s)	Gastrointestinal Neoplasms ; Humans ; Inflammation/drug therapy ; Intracellular Signaling Peptides and Proteins ; Obesity/drug therapy ; Orexin Receptors ; Orexins ; Receptors, G-Protein-Coupled ; Receptors, Neuropeptide
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Orexin Receptors ; Orexins ; Receptors, G-Protein-Coupled ; Receptors, Neuropeptide
Language	English
Publishing date	2021-06-30
Publishing country	United States
Document type	Editorial ; Review
ZDB-ID	2185929-2
ISSN	2219-2840 ; 1007-9327
ISSN (online)	2219-2840
ISSN	1007-9327
DOI	10.3748/wjg.v27.i44.7582
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Article: The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment.

Voisin, Thierry / Nicole, Pascal / Gratio, Valérie / Chassac, Anaïs / Mansour, Dounia / Rebours, Vinciane / Couvelard, Anne / Couvineau, Alain

Frontiers in oncology

2022 Volume 12, Page(s) 904327

Abstract: Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-associated death in the West. This type of cancer has a very poor prognosis notably due to the development of chemoresistance when treatments including gemcitabine and Abraxane ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-associated death in the West. This type of cancer has a very poor prognosis notably due to the development of chemoresistance when treatments including gemcitabine and Abraxane (Nab-paclitaxel) were prescribed. The identification of new treatment circumventing this chemoresistance represents a key challenge. Previous studies demonstrated that the activation of orexin receptor type 1 (OX1R), which was ectopically expressed in PDAC, by its natural ligand named orexin-A (OxA), led to anti-tumoral effect resulting in the activation of mitochondrial pro-apoptotic mechanism. Here, we demonstrated that OxA inhibited the pancreatic cancer cell (AsPC-1) growth and inhibited the tumor volume in preclinical models as effectively as gemcitabine and Nab-paclitaxel. Moreover, the combination therapy including OxA plus gemcitabine or OxA plus Nab-paclitaxel was additive on the inhibition of cancer cell growth and tumor development. More importantly, the treatment by OxA of chemoresistant tumors to gemcitabine or Nab-paclitaxel obtained by successive xenografts in mice revealed that OxA was able to induce a strong inhibition of tumor development, whereas no OxA resistance was identified in tumors. The OX1R/OxA system might be an innovative and powerful alternative treatment of chemoresistant PDAC.
Language	English
Publishing date	2022-06-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.904327
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Article: Orexins as Novel Therapeutic Targets in Inflammatory and Neurodegenerative Diseases.

Couvineau, Alain / Voisin, Thierry / Nicole, Pascal / Gratio, Valérie / Abad, Catalina / Tan, Yossan-Var

Frontiers in endocrinology

2019 Volume 10, Page(s) 709

Abstract: Orexins [orexin-A (OXA) and orexin-B (OXB)] are two isoforms of neuropeptides produced by the hypothalamus. The main biological actions of orexins, focused on the central nervous system, are to control the sleep/wake process, appetite and feeding, energy ...

Abstract	Orexins [orexin-A (OXA) and orexin-B (OXB)] are two isoforms of neuropeptides produced by the hypothalamus. The main biological actions of orexins, focused on the central nervous system, are to control the sleep/wake process, appetite and feeding, energy homeostasis, drug addiction, and cognitive processes. These effects are mediated by two G protein-coupled receptor (GPCR) subtypes named OX1R and OX2R. In accordance with the synergic and dynamic relationship between the nervous and immune systems, orexins also have neuroprotective and immuno-regulatory (i.e., anti-inflammatory) properties. The present review gathers recent data demonstrating that orexins may have a therapeutic potential in several pathologies with an immune component including multiple sclerosis, Alzheimer's disease, narcolepsy, obesity, intestinal bowel diseases, septic shock, and cancers.
Language	English
Publishing date	2019-10-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2019.00709
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Article ; Online: Identification of the Axis β-Catenin-BTK in the Dynamic Adhesion of Chronic Lymphocytic Leukemia Cells to Their Microenvironment.

Mihoub, Imane / Rharass, Tareck / Ouriemmi, Souhaïl / Oudar, Antonin / Aubard, Laure / Gratio, Valérie / Lazarian, Gregory / Ferreira, Jordan / Dondi, Elisabetta / Cymbalista, Florence / Levy, Vincent / Baran-Marszak, Fanny / Varin-Blank, Nadine / Ledoux, Dominique / Le Roy, Christine / Gardano, Laura

International journal of molecular sciences

2023 Volume 24, Issue 24

Abstract: In the microenvironment, cell interactions are established between different cell types to regulate their migration, survival and activation. β-Catenin is a multifunctional protein that stabilizes cell-cell interactions and regulates cell survival ... ...

Abstract	In the microenvironment, cell interactions are established between different cell types to regulate their migration, survival and activation. β-Catenin is a multifunctional protein that stabilizes cell-cell interactions and regulates cell survival through its transcriptional activity. We used chronic lymphocytic leukemia (CLL) cells as a cellular model to study the role of β-catenin in regulating the adhesion of tumor cells to their microenvironment, which is necessary for tumor cell survival and accumulation. When co-cultured with a stromal cell line (HS-5), a fraction of the CLL cells adhere to stromal cells in a dynamic fashion regulated by the different levels of β-catenin expression. In non-adherent cells, β-catenin is stabilized in the cytosol and translocates into the nucleus, increasing the expression of cyclin D1. In adherent cells, the level of cytosolic β-catenin is low but membrane β-catenin helps to stabilize the adhesion of CLL to stromal cells. Indeed, the overexpression of β-catenin enhances the interaction of CLL with HS-5 cells, suggesting that this protein behaves as a regulator of cell adhesion to the stromal component and of the transcriptional regulation of cell survival. Inhibitors that block the stabilization of β-catenin alter this equilibrium and effectively disrupt the support that CLL cells receive from the cross-talk with the stroma.
MeSH term(s)	Humans ; beta Catenin/genetics ; beta Catenin/metabolism ; Cell Communication ; Cell Line, Tumor ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Stromal Cells/metabolism ; Tumor Microenvironment ; Agammaglobulinaemia Tyrosine Kinase/metabolism
Chemical Substances	beta Catenin ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2)
Language	English
Publishing date	2023-12-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms242417623
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Article: The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role.

Couvineau, Alain / Dayot, Stéphanie / Nicole, Pascal / Gratio, Valérie / Rebours, Vinciane / Couvelard, Anne / Voisin, Thierry

Frontiers in endocrinology

2018 Volume 9, Page(s) 573

Abstract: Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central ... ...

Abstract	Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central effects, orexins also play a role in various peripheral organs such as the intestine, pancreas, adrenal glands, kidney, adipose tissue and reproductive tract.In the past few years, an unexpected anti-tumoral role of orexins mediated by a new signaling pathway involving the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in both orexin receptors subtypes, the recruitment of the phosphotyrosine phosphatase SHP2 and the induction of mitochondrial apoptosis has been elucidated. In the present review, we will discuss the anti-tumoral effect of orexin/OXR system in colon, pancreas, prostate and other cancers, and its interest as a possible therapeutic target.
Language	English
Publishing date	2018-09-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2018.00573
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Article ; Online: In vitro

Dayot, Stéphanie / Speisky, Daniela / Couvelard, Anne / Bourgoin, Pierre / Gratio, Valérie / Cros, Jérôme / Rebours, Vinciane / Sauvanet, Alain / Bedossa, Pierre / Paradis, Valérie / Ruszniewski, Philippe / Couvineau, Alain / Voisin, Thierry

Oncotarget

2018 Volume 9, Issue 6, Page(s) 6952–6967

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant
Language	English
Publishing date	2018-01-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.24084
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Article ; Online: Aberrant expression of proteinase-activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB-2 kinase.

Gratio, Valérie / Walker, Francine / Lehy, Thérèse / Laburthe, Marc / Darmoul, Dalila

International journal of cancer

2009 Volume 124, Issue 7, Page(s) 1517–1525

Abstract: Thrombin is now recognized as an important factor in many cancers. Here, we examined the expression and role of the recently discovered thrombin receptor PAR4, in human colon cancer cells. PAR4 mRNA was found in 10 out of 14 (71%) human colon cancer cell ...

Abstract	Thrombin is now recognized as an important factor in many cancers. Here, we examined the expression and role of the recently discovered thrombin receptor PAR4, in human colon cancer cells. PAR4 mRNA was found in 10 out of 14 (71%) human colon cancer cell lines tested but not in epithelial cells isolated from normal human colon. This finding is in line with immunostaining results of PAR4 in human colon tumors and its absence in normal human colonic mucosa. Investigation of the functional significance of the aberrant expression of PAR4 in colon cancer cells revealed (i) a prompt increase in intracellular calcium concentration on challenge with PAR4-specific agonist AP4 (100 microM) and (ii) marked mitogenic response (2.5-fold increase in cell number) in a dose-dependent manner on treatment with AP4 (0.1-300 microM). Analysis of the signaling pathways downstream of PAR4 activation in HT29 cells showed (i) a sustained phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2) and (ii) the involvement of epidermal growth factor receptor B-2 (ErbB-2) but not of epidermal growth factor receptor in PAR4-induced mitogen-activated protein kinase activation. Tyrphostin AG1478, the ErbB inhibitor, reversed the action of AP4 on ERK1/2 and ErbB-2 phosphorylation and HT29 cell growth. Finally, the Src inhibitor PP2 abrogated ErbB-2 and ERK phosphorylation and HT29 cell proliferation, suggesting the essential role of Src activity in PAR4-induced phosphorylation of ErbB-2. These data highlight the role of PAR4 as a new important player in the control of colon tumors and underline the critical role of ErbB-2 transactivation.
MeSH term(s)	Blotting, Western ; Calcium Signaling/drug effects ; Calcium Signaling/physiology ; Cell Line, Tumor ; Cell Proliferation ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Enzyme Inhibitors/pharmacology ; Fluorescent Antibody Technique ; HT29 Cells ; Humans ; Immunohistochemistry ; Immunoprecipitation ; RNA, Messenger/analysis ; Receptor, ErbB-2/drug effects ; Receptor, ErbB-2/metabolism ; Receptors, Thrombin/drug effects ; Receptors, Thrombin/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Transcriptional Activation ; src-Family Kinases/drug effects ; src-Family Kinases/metabolism
Chemical Substances	Enzyme Inhibitors ; RNA, Messenger ; Receptors, Thrombin ; protease-activated receptor 4 ; Receptor, ErbB-2 (EC 2.7.10.1) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2009-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.24070
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Zs.A 478: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation.

Darmoul, Dalila / Gratio, Valérie / Devaud, Hélène / Laburthe, Marc

The Journal of biological chemistry

2004 Volume 279, Issue 20, Page(s) 20927–20934

Abstract: Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor ...

Abstract	Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the signaling pathways downstream of PAR2 activation that lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events upon activation of PAR2 by the serine protease trypsin or the specific PAR2-activating peptide (AP2): (i) a matrix metalloproteinase-dependent release of transforming growth factor (TGF)-alpha, as demonstrated with TGF-alpha-blocking antibodies and measurement of TGF-alpha in culture medium; (ii) TGF-alpha-mediated activation of epidermal growth factor receptor (EGF-R) and subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent cell proliferation. The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-alpha-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R. These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation.
MeSH term(s)	Cell Division ; Cell Line, Tumor ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; ErbB Receptors/genetics ; ErbB Receptors/physiology ; Humans ; Kinetics ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation ; Protein Tyrosine Phosphatases/antagonists & inhibitors ; Quinazolines ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor, PAR-2/metabolism ; Transcriptional Activation ; Trypsin/metabolism ; Tyrphostins/pharmacology
Chemical Substances	Quinazolines ; Receptor, PAR-2 ; Tyrphostins ; RTKI cpd (170449-18-0) ; ErbB Receptors (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; Trypsin (EC 3.4.21.4)
Language	English
Publishing date	2004-03-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M401430200
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