Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target

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

doi:10.3390/molecules26164849

Cited by 13 publications

(27 citation statements)

References 71 publications

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“…Among this large family, we have demonstrated in 2011 that OX1R, but not OX2R, was ectopically expressed in colon cancer whatever its location and/or grade of development ( 15 ). The OX1R activation in colon cancer cells by exogenous orexins (OxA or OxB) induced the mitochondrial caspase-dependent apoptosis ( 28 ) The OxA/OX1R system was responsible for the anti-tumoral impact in preclinical models in which colon cancer cells were xenografted and also in preclinical models where pancreatic or liver cancer cells were xenografted ( 15 , 19 , 29 ). Usually, the first or second line of pancreatic cancer treatment, notably in metastatic pancreatic cancer, involved gemcitabine and Nab-paclitaxel ( 1 ).…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…In recent years, TRT has expanded to treat a wider range of targets and tumors in addition to thyroid, with a steadily increasing number of radiopharmaceuticals in preclinical and clinical development [ 19 , 20 , 73 , 74 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. Consequently, TRT represents an unprecedented opportunity for personalizing medical radiation by sex and hormonal status before rather than after the patients who are the most vulnerable (namely, young females) and can benefit most from individualized, well-informed therapy, become statistics in the large and long follow-up studies necessary to establish secondary cancer risks from medicinal irradiation.…”

Section: Sex Hormonal Status and Targeted Radionuclide Therapy: A Cha...mentioning

confidence: 99%

Modulation of Secondary Cancer Risks from Radiation Exposure by Sex, Age and Gonadal Hormone Status: Progress, Opportunities and Challenges

Biegon

Cohen

Franceschi

2022

JPM

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Available data on cancer secondary to ionizing radiation consistently show an excess (2-fold amount) of radiation-attributable solid tumors in women relative to men. This excess risk varies by organ and age, with the largest sex differences (6- to more than 10-fold) found in female thyroid and breasts exposed between birth until menopause (~50 years old) relative to age-matched males. Studies in humans and animals also show large changes in cell proliferation rates, radiotracer accumulation and target density in female reproductive organs, breast, thyroid and brain in conjunction with physiological changes in gonadal hormones during the menstrual cycle, puberty, lactation and menopause. These sex differences and hormonal effects present challenges as well as opportunities to personalize radiation-based treatment and diagnostic paradigms so as to optimize the risk/benefit ratios in radiation-based cancer therapy and diagnosis. Specifically, Targeted Radionuclide Therapy (TRT) is a fast-expanding cancer treatment modality utilizing radiopharmaceuticals with high avidity to specific molecular tumor markers, many of which are influenced by sex and gonadal hormone status. However, past and present dosimetry studies of TRT agents do not stratify results by sex and hormonal environment. We conclude that cancer management using ionizing radiation should be personalized and informed by the patient sex, age and hormonal status.

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“…Therefore, both endogenous orexins and OX1R have no impact on tumor growth, and they can only affect malignancy in the presence of exogenous orexins. [ 207 ] Despite the lack of orexins within tumors, OxA expression can be detected in “fiber‐like” stroma surrounding prostate tumors and follicular exocrine epithelia, [ 208 ] indicating a possible impact on tumor growth through stromal cells within the TME. Therefore, the orexin/OXR system probably acts through paracrine effects on cancerous cells.…”

Section: Neuropeptides and Their Receptors In Cancermentioning

confidence: 99%

“…Generally, the cAMP pathway activates relevant enzymes and regulates gene expression, JNK, ERK1/2, and PI3K/Akt activation triggers cell proliferation, cell cycle progression, and apoptosis suppression, while p38/MAPK participates in programmed cell death. [207,209] More recently, Voisin et al revealed that the orexin/OX1R system induced a mitochondrial apoptosis response, which is driven by a new signaling pathway including immunoreceptor tyrosine-based motifs (ITIM) and the tyrosine-protein phosphatase nonreceptor type (SHP2) both in Chinese hamster ovary (CHO) cells and colon cancer cells. [210] In conclusion, recent studies on orexin signaling provides a wide range of possibilities in the treatment of certain cancers; however, we are still at an early stage in this novel field and much future work is required.…”

Section: Orexins/hypocretinsmentioning

confidence: 99%

Neuropeptides in Cancer: Friend and Foe?

Berisha

Borniger

2022

Advanced Biology

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highly dynamic network of various cell types (e.g., cancer cells, endothelial cells, immune cells, fibroblasts) that exert differential effects on neuronal activity within the local environment. Thus, complex signaling between cancer and stromal cells in the TME results in altered firing rates of local nerves. Reciprocally, increased neuronal activity and subsequent release of classical neurotransmitters and/or neuropeptides within the TME results in enhanced cancer progression and subsequent metastasis in various preclinical models and clinical studies. [5][6][7][8][9] Nerves interact with multiple stromal cells in the TME where they indirectly promote tumor growth, progression, and subsequent metastasis. [10] Several studies have demonstrated that sympathetic nerve innervation and subsequent release of the neurotransmitter norepinephrine (NE) is increased in breast tumors. [6,8,9] However, recent work has demonstrated that there is an inverse relationship between tumor weight and norepinephrine content (i.e., larger the size of the tumor, the lower the levels of NE), despite increased innervation of sympathetic nerves within the TME. [11] These findings may be attributed to a relatively unexplored phenomenon: neuropeptide release within the TME. Neuropeptides are molecular messengers that regulate a variety of functions in the central and peripheral nervous systems via binding G-protein-coupled receptors (GPCRs) on target cells. One of the many functions of neuropeptides is serving as growth factors for normal cells via the activation of the heterotrimeric G protein Gq and subsequent synthesis of second messengers and engagement of tyrosine phosphorylation cascades. Neuropeptides act as neuromodulators, in that they can alter the response of neurons to neurotransmitters and other circulating signals, such as leptin, ghrelin, glucose, and insulin-all of which are affected during cancer progression. [12][13][14][15][16][17] For example, both neuropeptide Y (NPY) and hypocretin/orexin neurons appear to mediate some of the orexigenic effects of centrally administered ghrelin as administration of NPY receptor antagonists attenuated ghrelininduced feeding. Similarly, ghrelin-induced feeding was suppressed in orexin knockout mice, indicating that ghrelin may stimulate feeding through both the orexin and NPY systems. [18] However, neuropeptide signaling is exploited within cancer cells and many studies demonstrate the contribution of neuropeptides in tumor cell proliferation and migration, [19] with many major neuropeptides also potentially contributing to cancer processes (see Table 1). Additionally, neuropeptides exert direct Neuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptid...

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Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target

Cited by 13 publications

References 71 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

Modulation of Secondary Cancer Risks from Radiation Exposure by Sex, Age and Gonadal Hormone Status: Progress, Opportunities and Challenges

Neuropeptides in Cancer: Friend and Foe?

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