Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions

Couvineau, Alain; Voisin, Thierry; Nicole, Pascal; Gratio, Valérie; Blais, Anne

doi:10.3748/wjg.v27.i44.7582

Cited by 17 publications

(22 citation statements)

References 112 publications

(167 reference statements)

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“…Since several years, our group demonstrated that orexin receptor type 1 (OX1R) but not orexin receptor type 2 (OX2R) was expressed in digestive cancer cells including pancreatic, colon, and liver cancers ( 14 ) where its activation by orexins induced a mitochondrial apoptosis leading to anti-tumoral impact of orexin/OX1R system ( 15 ). Orexins specifically activated two receptor subtypes belonging to the G-protein-coupled receptor (GPCR) family ( 16 ). Orexins, encompassing two isoforms named orexin-A (OxA) and orexin-B (OxB), are hypothalamic neuropeptides produced by the same precursor, the prepro-orexin ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…Orexins specifically activated two receptor subtypes belonging to the G-protein-coupled receptor (GPCR) family ( 16 ). Orexins, encompassing two isoforms named orexin-A (OxA) and orexin-B (OxB), are hypothalamic neuropeptides produced by the same precursor, the prepro-orexin ( 16 ). The main biological function of orexins was to control the wakefulness ( 17 ), and a dysregulation of this function led to human narcolepsy type I pathology ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment

et al. 2022

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment

et al. 2022

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“…The effect of CRF is cancer-type specific: CRF binding to the CRF receptor can potentiate an anti-tumor response in endometrial cancer 45 and promote cancer progression in colon cancer 46 or breast cancer for instance 41 . Orexin receptors are expressed in gastric cancer (including esophageal cancer) and treatment with orexin has been shown to induce apoptosis in colorectal, neuroblastoma and pancreatic cancer cells 43 . Orexin A was even able to induce apoptosis in drug resistant colorectal cancer cell lines 47 .…”

Section: Resultsmentioning

confidence: 99%

“…In particular, the Corticotropin Releasing Hormone (CRH) signaling pathway and the orexin receptor pathway were upregulated in a subspace of the ESCC latent space. These pathways have been previously shown to be overexpressed in several cancers and can be used for targeted therapy [41][42][43][44] .…”

Section: Cansig Rediscovers Previously Investigated Signatures In Thr...mentioning

confidence: 99%

CanSig: a tool for benchmarking malignant state discovery in single-cell RNA-Seq data

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Barkmann

Czyz

et al. 2022

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Human tumors are highly heterogeneous in their cell composition; specifically, they exhibit heterogeneity in transcriptional states of malignant cells, as has been recently discovered through single-cell RNA sequencing (scRNA-seq). Distinct states of malignant cells have been linked to variability in tumorigenic properties and resistance to anti-cancer treatment. Despite the fact that scRNA-seq data contain all necessary information to uncover shared transcriptional states of malignant cells in tumors, jointly analyzing cells from multiple cancer patients comes with its set of challenges including batch correction and accounting for patient-specific genetic background driving differences between gene expression vectors. We propose CanSig, an easy-to-use approach designed to discover known and de novo shared signatures in cancer single cells. CanSig preprocesses, integrates and analyzes scRNA-seq data to provide new signatures of shared transcriptional states and links these states to known pathways. We show that CanSig successfully rediscovers ground truth pathways determining shared transcriptional states in two simulated and three experimental datasets; the latter spanning 135 patients and 72,000 cells. We then illustrate CanSig's investigative potential by discovering novel signatures in esophageal squamous cell carcinoma possibly linked to targeted patient treatment; we also point out a de novo signature in breast cancer predictive of patients' survival. In the cancer types studied, we juxtapose copy number variation with discovered shared transcriptional states and uncover a genetic component predisposing cancer cells to activation of specific transcriptional programs. In sum, CanSig, specifically developed to analyze shared transcriptional heterogeneity of malignant cells of different genetic backgrounds, can greatly facilitate the exploratory analysis of scRNA-seq cancer data and efficiently identify novel transcriptional signatures linked to known biological pathways.

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“…Beyond these CNS actions, orexins and their receptors had biological impacts in peripheral nervous system (PNS). Although less investigated, the role of orexin in PNS ( Figure 1 ) revealed actions on neuroendocrine functions, blood pressure, metabolism, reproductive functions, energy balance and gastrointestinal motility ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

The Orexin receptors: Structural and anti-tumoral properties

et al. 2022

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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.

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Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions

Cited by 17 publications

References 112 publications

The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment

The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment

CanSig: a tool for benchmarking malignant state discovery in single-cell RNA-Seq data

The Orexin receptors: Structural and anti-tumoral properties

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